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OBJECTIVE: To identify the facilitators of and barriers to the implementation of Community Pharmacists-Led Anticoagulation Management Services (CPAMS). DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL Register of Controlled Trials were searched from inception until August 20, 2021. STUDY SELECTION AND DATA EXTRACTION: All abstracts proceeded to full-text review, which was completed by 2 reviewers. Data extraction was completed by a single reviewer and verified. Analysis was completed using best-fit framework synthesis. DATA SYNTHESIS: A total of 17 articles reporting on CPAMS from 6 jurisdictions were included: 2 Canadian provincial programs (Nova Scotia, Alberta), a national program (New Zealand), and 3 cities in the United Kingdom (Whittington and Brighton and Hove) and Australia (Sydney). Facilitators of CPAMS included convenience for patients, accessibility for patients, professional satisfaction for pharmacists, increased efficiency in anticoagulation management, improved outcomes, enhanced collaboration, and scalability. Barriers included perceived poor quality of care by patients, resistance by general practitioners, organizational limits, capping of the number of eligible patients, and cost. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The barriers and facilitators identified in this review will inform health policy makers on the implementation and improvement of CPAMS for patients and health care practitioners. CONCLUSION AND RELEVANCE: CPAMS has been implemented in 6 jurisdictions across 4 countries, with reported benefits and challenges. The programs were structurally similar in most jurisdictions, with minor variations in implementation. New anticoagulation management programs should consider adapting existing frameworks to local needs.
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Anticoagulantes , Farmacéuticos , Alberta , Anticoagulantes/uso terapéutico , Australia , HumanosRESUMEN
OBJECTIVES: To describe the state of the literature for clinical effectiveness of neurostimulation used for the management of chronic pain. METHODS: A systematic review of spinal cord stimulation (SCS), peripheral nerve stimulation (PNS), peripheral nerve field stimulation (PNFS), and supraorbital transcutaneous electrical nerve stimulation in patients with cancer and noncancer chronic pain was conducted. MEDLINE, Embase, CINAHL, and the Cochrane CENTRAL Register of Controlled Trials were searched, using terms like "electrical stimulation therapy" and "pain management." Direction of effect, consistency across studies, and strength of evidence for effects of neurostimulation on chronic pain were narratively synthesized. RESULTS: A total of 15 randomized controlled trials (RCTs) examining SCS, 7 RCTs examining PNS/PNFS, and 1 nonrandomized trial examining supraorbital transcutaneous electrical nerve stimulation (TENS) were included. In nine SCS studies, neurostimulation had positive effects on pain. In three studies, neurostimulation did not significantly reduce pain. For PNS/PNFS, five studies found improvements in pain offered by neurostimulation; pain outcomes were not reported in two studies. In the TENS study, neurostimulation reduced headaches per month and medication consumption. Overall, 21 studies were of low or unclear risk of bias, 4 were high risk of bias, and the TENS study was not appropriate for assessment using the Cochrane Risk of Bias tool. CONCLUSIONS: A robust body of evidence examining SCS and PNS was identified. Only one study for PNFS and TENS was identified; both reported pain reductions. Generally, neurostimulation improved pain control. Future studies should examine the effectiveness of neurostimulation offered early in the trajectory of chronic pain.
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Dolor Crónico/terapia , Neuroestimuladores Implantables , Manejo del Dolor/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Estimulación de la Médula Espinal/métodos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Dolor Crónico/diagnóstico , Terapia por Estimulación Eléctrica/métodos , Humanos , Dimensión del Dolor/métodos , Resultado del TratamientoRESUMEN
PURPOSE: Ultrasound-guided spinal injections are less common than fluoroscopy-guided injections. Although unable to penetrate bones, ultrasound guidance has a number of advantages including convenience and reduced exposure to ionizing radiation. However, it is not known how ultrasound-guided injections compare to fluoroscopy-guided injections in the management of lower back pain. Our objective is to systematically review the literature comparing ultrasound-guided injections to fluoroscopy-guided injections for the management of lower back pain. METHODS: Medline, Cochrane CENTRAL Register of Controlled Trials, Embase, and NHSEED were searched from 2007 to September 26, 2017. Inclusion criteria included (1) randomized controlled trial design, (2) compared ultrasound-guided and fluoroscopy-guided injections for lower back pain, (3) dose and volume of medications injected were identical between trial arms, and (4) reported original data. RESULTS: One hundred one unique records were identified, and 21 studies were considered for full-text inclusion. Nine studies formed the final data set. Studies comparing ultrasound- and fluoroscopy-guided injections for lower back pain management reported no difference in pain relief, procedure time, number of needle passes, changes in disability indices, complications or adverse events, post-procedure opioid consumption, or patient satisfaction. CONCLUSION: Fluoroscopic guidance of injections for the management of lower back pain is similar in efficacy to ultrasound guidance. The exact role of ultrasound guidance needs to be further studied, especially for nerve root injections, where safety is the major concern. KEY POINTS: ⢠There were no differences in pain relief, procedure time, number of needle passes, changes in disability indices, complications or adverse events, post-procedure opioid consumption, or patient satisfaction between ultrasound- and fluoroscopy-guided injections for the management of lower back pain. ⢠Given the lack of evidence to demonstrate superior efficacy and the added harms with fluoroscopic guidance, ultrasound guidance may be the preferred method of guidance for injections to manage lower back pain in appropriate patients. Further study is required to understand the exact role of ultrasound in image-guided injections.
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Fluoroscopía/métodos , Dolor de la Región Lumbar/diagnóstico por imagen , Dolor de la Región Lumbar/tratamiento farmacológico , Ultrasonografía Intervencional/métodos , Anestésicos Locales/administración & dosificación , Quimioterapia Combinada , Glucocorticoides/administración & dosificación , Humanos , Inyecciones Epidurales , Manejo del Dolor/métodos , Radiografía Intervencional/métodosRESUMEN
BACKGROUND: The aim of palliative care is to improve the quality of life of patients and families through the prevention and relief of suffering. Frequently, patients may choose to receive palliative care in the home. The objective of this paper is to summarize the quality and primary outcomes measured within the palliative care in the home literature. This will synthesize the current state of the literature and inform future work. METHODS: A scoping review was completed using PRISMA guidelines. PubMed, Embase, CINAHL, Web of Science, Cochrane Library, EconLit, PsycINFO, Centre for Reviews and Dissemination, Database of Abstracts of Reviews of Effects, and National Health Service Economic Evaluation Database were searched from inception to August 2016. Inclusion criteria included: 1) care was provided in the "home of the patient" as defined by the study, 2) outcomes were reported, and 3) reported original data. Thematic component analysis was completed to categorize interventions. RESULTS: Fifty-three studies formed the final data set. The literature varied extensively. Five themes were identified: accessibility of healthcare, caregiver support, individualized patient centered care, multidisciplinary care provision, and quality improvement. Primary outcomes were resource use, symptom burden, quality of life, satisfaction, caregiver distress, place of death, cost analysis, or described experiences. The majority of studies were of moderate or unclear quality. CONCLUSIONS: There is robust literature of varying quality, assessing different components of palliative care in the home interventions, and measuring different outcomes. To be meaningful to patients, these interventions need to be consistently evaluated with outcomes that matter to patients. Future research could focus on reaching a consensus for outcomes to evaluate palliative care in the home interventions.
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Servicios de Atención de Salud a Domicilio/normas , Evaluación de Resultado en la Atención de Salud/métodos , Cuidados Paliativos/normas , Calidad de Vida/psicología , Humanos , Cuidados Paliativos/métodosRESUMEN
BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1(En-/-)) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. METHODS AND RESULTS: DDAH1 deletion in the DDAH1(En-/-) mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1(En-/-) mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1(En-/-) mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. CONCLUSIONS: We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.
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Amidohidrolasas/fisiología , Células Endoteliales/enzimología , Endotelio Vascular/enzimología , Hemodinámica/fisiología , Homeostasis/fisiología , Neovascularización Fisiológica/fisiología , Amidohidrolasas/deficiencia , Animales , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
OBJECTIVE: Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl-L-arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl-L-arginine is dimethylarginine dimethylaminohydrolase (DDAH). The first isoform dimethylarginine dimethylaminohydrolase 1 has previously been shown to be an important regulator of methylarginines in both health and disease. This study explores for the first time the role of endogenous dimethylarginine dimethylaminohydrolase 2 in regulating cardiovascular physiology and also determines the functional impact of dimethylarginine dimethylaminohydrolase 2 deletion on outcome and immune function in sepsis. APPROACH AND RESULTS: Mice, globally deficient in Ddah2, were compared with their wild-type littermates to determine the physiological role of Ddah2 using in vivo and ex vivo assessments of vascular function. We show that global knockout of Ddah2 results in elevated blood pressure during periods of activity (mean [SEM], 118.5 [1.3] versus 112.7 [1.1] mm Hg; P=0.025) and changes in vascular responsiveness mediated by changes in methylarginine concentration, mean myocardial tissue asymmetric dimethylarginine (SEM) was 0.89 (0.06) versus 0.67 (0.05) µmol/L (P=0.02) and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome (120-hour survival was 12% in Ddah2 knockouts versus 53% in wild-type animals; P<0.001). Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals. CONCLUSIONS: Ddah2 has a regulatory role both in normal physiology and in determining outcome of severe polymicrobial sepsis. Elucidation of this role identifies a mechanism for the observed relationship between Ddah2 polymorphisms, cardiovascular disease, and outcome in sepsis.
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Amidohidrolasas/metabolismo , Hemodinámica , Óxido Nítrico/biosíntesis , Sepsis/fisiopatología , Animales , Carga Bacteriana , Presión Sanguínea , Modelos Animales de Enfermedad , Macrófagos Peritoneales/metabolismo , Ratones Noqueados , Pronóstico , Sepsis/metabolismo , Sepsis/microbiología , Análisis de Secuencia de ARN , TelemetríaRESUMEN
OBJECTIVE: Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. METHODS AND RESULTS: In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). CONCLUSIONS: Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure.
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Arginina/análogos & derivados , Presión Sanguínea/fisiología , Óxido Nítrico/metabolismo , Transaminasas/fisiología , Adulto , Animales , Arginina/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión/fisiopatología , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Mitocondrias/metabolismo , Transaminasas/deficiencia , Transaminasas/genéticaRESUMEN
Asymmetric dimethylarginine (ADMA) is generated through the irreversible methylation of arginine residues. It is an independent risk factor for cardiovascular disease, currently thought to be due to its ability to act as a competitive inhibitor of the nitric oxide (NO) synthase enzymes. Plasma ADMA concentrations increase with obesity and fall following weight loss; however, it is unknown whether they play an active role in adipose pathology. Here, we demonstrate that ADMA drives lipid accumulation through a newly identified NO-independent pathway via the amino-acid sensitive calcium-sensing receptor (CaSR). ADMA treatment of 3T3-L1 and HepG2 cells upregulates a suite of lipogenic genes with an associated increase in triglyceride content. Pharmacological activation of CaSR mimics ADMA while negative modulation of CaSR inhibits ADMA driven lipid accumulation. Further investigation using CaSR overexpressing HEK293 cells demonstrated that ADMA potentiates CaSR signalling via Gq intracellular Ca2+ mobilisation. This study identifies a signalling mechanism for ADMA as an endogenous ligand of the G protein-coupled receptor CaSR that potentially contributes to the impact of ADMA in cardiometabolic disease.
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Arginina , Receptores Sensibles al Calcio , Humanos , Células HEK293 , Arginina/metabolismo , Óxido Nítrico Sintasa/metabolismo , LípidosRESUMEN
Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1-/- explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.
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Glicoproteínas , Interleucina-6 , Neovascularización Patológica , Factor de Transcripción STAT3 , COVID-19 , Células Endoteliales/metabolismo , Glicoproteínas/metabolismo , Humanos , Interleucina-6/metabolismo , Neovascularización Patológica/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
OBJECTIVE: To examine the lived experience of extracorporeal membrane oxygenation (ECMO) by patients and their families, and their relationship with intensive care clinicians. RESEARCH METHODOLOGY: Semi-structured interviews were conducted with six patients who had received ECMO and with four of their family members. The data were analysed narratively using a constant comparative method. SETTING: Patients were treated at a major acute care hospital in British Columbia between 2014 and 2021. ECMO was used either as a bridge to recovery or to organ transplant. Four had family members bedside throughout, while two had virtual visits due to COVID-19 infection control measures. FINDINGS: ECMO was experienced through a triad of relationships between the patient, key family members and key clinicians. The strength, directionality and focus of these relationships shifted during therapy and realigned once ECMO was removed. The largest shift involved family members. Post-ECMO, patients relied almost entirely on spouses, adult children and clinical team members to reconstruct their experience. The connection between families and clinical team members was limited and changed little. CONCLUSIONS: The lived experience of ECMO was complex in ways yet to be comprehensively reported in the literature. This technology had particular impact on family members when ECMO was used as a bridge to transplant and where run times extended to multiple weeks. COVID-19 infection control restrictions further complicated how this technology was experienced. Findings from this study highlight the importance of intensive care nurses recognising the critical role family members play as witnesses whose experiences later allow patients to make sense of their journey post-discharge.
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COVID-19 , Oxigenación por Membrana Extracorpórea , Adulto , Cuidados Posteriores , Niño , Oxigenación por Membrana Extracorpórea/efectos adversos , Familia , Humanos , Alta del Paciente , Estudios RetrospectivosRESUMEN
OBJECTIVES: Diabetic retinopathy is a common microvascular complication that leads to vision loss. Despite national and international organizations developing guidelines for diabetic retinopathy screening, patients with diabetes remain unscreened. Our aim was to understand facilitators and barriers influencing diabetic retinopathy screening attendance and to examine factors that promote program success. METHODS: MEDLINE, Embase, PsycINFO and CINAHL from inception until September 23, 2019, were used for data collection. Studies were included if they were original qualitative research articles, included adults >18 years of age and assessed diabetic retinopathy screening programs or retinopathy screening as a component of a general diabetes care program. A "best-fit" framework synthesis methodology was used for this analysis. RESULTS: Twenty-nine articles involving 1,433 participants were identified. Six themes of barriers to, and facilitators of, diabetic retinopathy screening were identified, including access to screening, knowledge and information sharing, training and skills competency, service delivery, cultural competency and psychological factors. Cost and competing interests were common barriers to access; lack of knowledge about screening services was also a frequently reported barrier. Both patients and providers identified the need for improved service delivery, especially the referral and follow-up process. Providers recognized the need for additional training, patients enumerated several psychological barriers to screening uptake and cultural considerations were believed to be important, particularly among Indigenous communities. CONCLUSIONS: To improve screening uptake, the identified challenges must be addressed while also reinforcing the facilitators. Furthermore, program administrators could model new and unsuccessful screening programs after the successful ones while also considering local peculiarities.
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Diabetes Mellitus , Retinopatía Diabética , Adulto , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Humanos , Tamizaje Masivo , Investigación CualitativaRESUMEN
Importance: Low-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages. Objective: To compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages. Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020. Study Selection: All comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included. Data Extraction and Synthesis: Data were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted. Main Outcomes and Measures: Primary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events. Results: A total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13â¯759 total participants, and 1 study was a cohort study of 164â¯021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses. Conclusions and Relevance: These findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.
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Anticuerpos Antivirales/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Escalofríos/epidemiología , Relación Dosis-Respuesta Inmunológica , Fiebre/epidemiología , Pruebas de Inhibición de Hemaglutinación , Humanos , Inmunogenicidad Vacunal , Reacción en el Punto de Inyección/epidemiología , Inyecciones Intradérmicas , Inyecciones Intramusculares , SeroconversiónRESUMEN
BACKGROUND: Despite their popularity, the efficacy of interventions targeting gut microbiota to improve depressive symptoms is unknown. Our objective is to summarize the effect of microbiome-targeting interventions on depressive symptoms. METHODS: We conducted a systematic review and meta-analysis. We searched MEDLINE, Embase, PsycINFO, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews and the Cochrane Controlled Register of Trials from inception to Mar. 5, 2021. We included studies that evaluated probiotic, prebiotic, synbiotic, paraprobiotic or fecal microbiota transplant interventions in an adult population (age ≥ 18 yr) with an inactive or placebo comparator (defined by the absence of active intervention). Studies must have measured depressive symptoms with a validated scale, and used a randomized controlled trial study design. We conducted a random effects meta-analysis of change scores, using standardized mean difference as the measure of effect. RESULTS: Sixty-two studies formed the final data set, with 50 included in the meta-analysis. Probiotic, prebiotic, and synbiotic interventions on depressive symptoms showed statistically significant benefits. In the single studies evaluating each of fecal microbiota transplant and paraprobiotic interventions, neither showed a statistically significant benefit. INTERPRETATION: Despite promising findings of benefit of probiotic, prebiotic and synbiotic interventions for depressive symptoms in study populations, there is not yet strong enough evidence to favour inclusion of these interventions in treatment guidelines for depression. Critical questions about species administered, dosage and timing relative to other antidepressant medications remain to be answered. STUDY REGISTRATION: PROSPERO no. 143178.
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Depresión/dietoterapia , Depresión/microbiología , Trasplante de Microbiota Fecal/métodos , Microbioma Gastrointestinal/efectos de los fármacos , Simbióticos/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility. METHODS: Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated. FINDINGS: In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active. CONCLUSIONS: LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics. FUNDING: Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366).
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Células Endoteliales , Neoplasias , Animales , Células Endoteliales/metabolismo , Glicoproteínas/genética , Inmunoterapia , Ratones , Neoplasias/terapia , Neovascularización Patológica/genética , Microambiente TumoralRESUMEN
Chronic pain has far-reaching impacts on a person's life and on society more broadly. After failure or intolerance of conservative treatments, neuromodulation may be an option for a subgroup of patients. However, little is known about the patient experience of neuromodulation. We conducted a systematic review of published qualitative research on patient experience with neuromodulation for chronic pain. Four databases were searched: MEDLINE, EMBASE, Psych INFO, and all EMB reviews, from inception to December 4, 2019. We used narrative synthesis to identify key findings from the included studies. The data were qualitatively analyzed using a modified constant comparative analysis to identify key themes across the studies. Seven thousand five hundred forty-two unique citations were retrieved. Sixty-four abstracts were selected by the reviewers and continued to full-text review. After full-text review, 57 studies were excluded with 7 studies included in this systematic review. The included studies were of high quality. Four broad themes emerged: (1) living with chronic pain, (2) expectations, (3) managing challenges, and (4) regaining normalcy. Neuromodulation should be part of an overall pain management plan that may include the need for ongoing emotional and psychosocial support. A deeper knowledge of the patient experience with neuromodulation will assist care teams in providing meaningful support to patients. The results of this study suggest that further research is needed to support neuromodulation as an option for patients living with chronic pain.
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Dolor , Humanos , Investigación CualitativaRESUMEN
Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including hypertension, obesity and hypertriglyceridemia. In this review, we discuss the clinical literature that link ADMA concentrations to increased risk of the development of atherosclerosis. The formation of atherosclerotic lesions relies on the interplay between vascular dysfunction, leading to endothelial activation and the accumulation of inflammatory cells, particularly macrophages, within the vessel wall. Here, we review the mechanisms through which elevated ADMA contributes to endothelial dysfunction, activation and reactive oxygen species (ROS) production; how ADMA may affect vascular smooth muscle phenotype; and finally whether ADMA plays a regulatory role in the inflammatory processes occurring within the vessel wall.
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BACKGROUND: With impending marijuana legislation in Canada, a broad understanding of the harms associated with marijuana use is needed to inform the clinical community and public, and to support evidence-informed public policy development. The purpose of the review was to synthesize the evidence on adverse health effects and harms of marijuana use. METHODS: We searched MEDLINE, The Cochrane Database of Systematic Reviews, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and the Health Technology Assessment Database from the inception of each database to May 2018. Given that systematic reviews evaluating one or other specific harm have been published, this is an overview review with the primary objective of assessing a health effect or harm. Data on author, country and year of publication, search strategy and results, and outcomes were extracted. Quality was assessed using the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist. RESULTS: The final analysis included 68 reviews. Evidence of harm was reported in 62 reviews for several mental health disorders, brain changes, cognitive outcomes, pregnancy outcomes and testicular cancer. Inconclusive evidence was found for 20 outcomes (some mental health outcomes, other types of cancers and all-cause mortality). No evidence of harm was reported for 6 outcomes. INTERPRETATION: Harm was associated with most outcomes assessed. These results should be viewed with concern by physicians and policy-makers given the prevalence of use, the persistent reporting of a lack of recognition of marijuana as a possibly harmful substance and the emerging context of legalization for recreational use.
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OF BACKGROUND DATA: In the general population, it has been estimated that 1.5% of people have ≥1 Tarlov cysts, with about 13% of those being symptomatic. Despite a range of options for treatment, there is debate about when, and how to optimally treat individuals with Tarlov cysts among clinicians, and among policy decision makers. OBJECTIVE: To summarize the current evidence on surgical treatment of Tarlov cysts. STUDY DESIGN: A systematic review was completed. METHODS: Nine databases were searched. Abstracts and full-texts were assessed by 2 reviewers. To be included, studies had to assess safety, efficacy, or effectiveness of treating Tarlov cysts, had to be written in English or French, and had to be a randomized, quasi-randomized, observational cohort, case control, or case series design including ≥2 participants. Logistic regression analysis was undertaken on the patient-level data collected to assess the association of patient and cyst characteristics on treatment success. RESULTS: In total, 31 studies were included in this systematic review; all were case series. Among the 646 participants included in these 31 studies, 210 experienced complete resolution of symptoms (32%), 327 had partial resolution (50%), 106 did not have any improvement or worsening of symptoms (16%), and 3 had their symptoms worsen after surgery (0.4%). A number of adverse events were reported after surgery; however, all were temporary. The analysis of 49 patients with data on cyst size resulted in the odds of complete resolution of symptoms being lower for patients with larger cysts (odds ratio=0.53, P-value=0.107) although this finding is not statistically significant. For those with a cyst >1.5 cm the odds of complete resolution were (odds ratio=0.36, P-value=0.190) compared with those with a cyst <1.5 cm. CONCLUSIONS: The evidence suggests that surgery for symptomatic Tarlov cysts may be an effective option for partially or completely relieving symptoms. Contrary to previous findings larger cysts were not associated with completely relieving symptoms.
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Quistes de Tarlov/cirugía , Humanos , Modelos Logísticos , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the impact of behaviour modification interventions to promote restrictive red blood cell (RBC) transfusion practices. DESIGN: Systematic review and meta-analysis. SETTING, PARTICIPANTS, INTERVENTIONS: Seven electronic databases were searched to January 2018. Published randomised controlled trials (RCTs) or non-randomised studies examining an intervention to modify healthcare providers' RBC transfusion practice in any healthcare setting were included. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was the proportion of patients transfused. Secondary outcomes included the proportion of inappropriate transfusions, RBC units transfused per patient, in-hospital mortality, length of stay (LOS), pretransfusion haemoglobin and healthcare costs. Meta-analysis was conducted using a random-effects model and meta-regression was performed in cases of heterogeneity. Publication bias was assessed by Begg's funnel plot. RESULTS: Eighty-four low to moderate quality studies were included: 3 were RCTs and 81 were non-randomised studies. Thirty-one studies evaluated a single intervention, 44 examined a multimodal intervention. The comparator in all studies was standard of care or historical control. In 33 non-randomised studies, use of an intervention was associated with reduced odds of transfusion (OR 0.63 (95% CI 0.56 to 0.71)), odds of inappropriate transfusion (OR 0.46 (95% CI 0.36 to 0.59)), RBC units/patient weighted mean difference (WMD: -0.50 units (95% CI -0.85 to -0.16)), LOS (WMD: -1.14 days (95% CI -2.12 to -0.16)) and pretransfusion haemoglobin (-0.28 g/dL (95% CI -0.48 to -0.08)). There was no difference in odds of mortality (OR 0.90 (95% CI 0.80 to 1.02)). Protocol/algorithm and multimodal interventions were associated with the greatest decreases in the primary outcome. There was high heterogeneity among estimates and evidence for publication bias. CONCLUSIONS: The literature examining the impact of interventions on RBC transfusions is extensive, although most studies are non-randomised. Despite this, pooled analysis of 33 studies revealed improvement in the primary outcome. Future work needs to shift from asking, 'does it work?' to 'what works best and at what cost?' PROSPERO REGISTRATION NUMBER: CRD42015024757.
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Transfusión de Eritrocitos/métodos , Investigación sobre Servicios de Salud/normas , Pautas de la Práctica en Medicina , Terapia Conductista , Transfusión de Eritrocitos/psicología , HumanosRESUMEN
Background and Aims. The lived experience of HCV has not been well documented in the literature. The aim of this systematic review was to understand the experiences of living with Hepatitis C Virus (HCV). Methods. Five databases were searched from inception until January 19, 2015. Studies were included if they focused on adults diagnosed with HCV; reported experience living with HCV; and described original research. Results. 46 studies were included. Studies found that participants had reduced quality of life due to physical symptoms. Due to physical symptoms and discrimination, many participants switched to part-time work or quit their jobs. Many individuals reported negative experiences with the healthcare system; themes of feeling unsupported, not having adequate information, and not feeling involved in decisions were reported. Stigma significantly impacted those living with HCV. Conclusions. Published literature indicates that those with HCV often feel stigmatized and unsupported in their care, relationships, and work environments, while simultaneously coping with physical and psychological symptoms. This synthesis points to areas where greater education, compassion, and patient-centered healthcare could improve the experience of people living with HCV.