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Frontiers in Oncology 2022The prevalence of Merkel cell polyomavirus(MCPyV) in Merkel cell carcinoma(MCC) and non-MCC skin lesions and its possible role in the etiology of other skin diseases...
The prevalence of Merkel cell polyomavirus(MCPyV) in Merkel cell carcinoma(MCC) and non-MCC skin lesions and its possible role in the etiology of other skin diseases remain controversial. To systematically assess the association between MCPyV infection and MCC, non-MCC skin lesions, and normal skin. For this systematic review and meta-analysis, a comprehensive search for eligible studies was conducted using Medline Ovid, Pubmed, Web of Science, and the Cochrane CENTRAL databases until August 2021; references were searched to identify additional studies. Observational studies that investigated the association between MCPyV infection and MCC, non-MCC skin lesions, and normal skin using polymerase chain reaction(PCR) as a detection method and provided sufficient data to calculate the prevalence of MCPyV positivity. A total of 50 articles were included in the study after exclusion criteria were applied. Two reviewers independently reviewed and assessed the eligibility of the studies, and all disagreements were resolved by consensus. To determine the association between MCPyV and MCC, overall odds ratio (OR) were calculated with 95% CI using a random-effects model. Single-arm meta-analyses were performed to examine the prevalence rate of MCPyV+ in MCC, non-MCC skin lesions, and normal skin. The primary analysis was the prevalence rate of MCPyV+ in MCC. Secondary outcomes included the prevalence rate of MCPyV+ in non-MCC skin lesions and normal skin. A total of 50 studies involving 5428 patients were reviewed based on our inclusion and exclusion criteria. Compared with the control group, MCPyV infection was significantly associated with MCC (OR = 3.51, 95% CI = 2.96 - 4.05). The global prevalence of MCPyV+ in MCC, melanoma, squamous cell carcinoma, basal cell carcinoma, Bowen's disease, actinic keratosis, keratoacanthoma, seborrheic keratosis, and normal skin was 80%, 4%, 15%, 15%, 21%, 6%, 20%, 10%, and 11%, respectively. The current results suggest that MCPyV infection is significantly associated with an increased risk of MCC. However, the low prevalence rate of MCPyV+ in non-MCC skin lesions does not exclude a pathogenic association of this virus with the development of non-MCC skin lesions.
PubMed: 35392226
DOI: 10.3389/fonc.2022.868781 -
The Cochrane Database of Systematic... Jun 2013Bowen's disease is the clinical term for in situ squamous cell carcinoma of the skin. Cutaneous lesions present as largely asymptomatic, well-defined, scaly erythematous... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bowen's disease is the clinical term for in situ squamous cell carcinoma of the skin. Cutaneous lesions present as largely asymptomatic, well-defined, scaly erythematous patches on sun-exposed skin. In general, people with Bowen's disease have an excellent prognosis because the disease is typically slow-growing and responds favourably to treatment. Lesions are persistent and can be progressive, with a small potential (estimated to be 3%) to develop into invasive squamous cell carcinoma. The relative effectiveness of the available treatments is not known for Bowen's disease, and this review attempts to address which is the most effective intervention, with the least side-effects, for cutaneous Bowen's disease.
OBJECTIVES
To assess the effects of therapeutic interventions for cutaneous Bowen's disease.
SEARCH METHODS
We searched the following databases up to September 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 9), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), and LILACS (from 1982). We also searched online trials registers. We checked the bibliographies of included and excluded studies and reviews, for further references to relevant randomised controlled trials (RCTs).
SELECTION CRITERIA
We included all randomised controlled trials assessing interventions used in Bowen's disease, preferably histologically proven.
DATA COLLECTION AND ANALYSIS
Two authors independently carried out study selection and assessment of methodological quality.
MAIN RESULTS
The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. Our secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at > 12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician.We included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53).Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants.One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma.
AUTHORS' CONCLUSIONS
Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU.The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.
Topics: Aminolevulinic Acid; Aminoquinolines; Antineoplastic Agents; Bowen's Disease; Cryotherapy; Fluorouracil; Humans; Imiquimod; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms; Treatment Outcome
PubMed: 23794286
DOI: 10.1002/14651858.CD007281.pub2 -
Journal of the European Academy of... Jan 2023Keratinocyte skin cancers are the most frequent malignancy, accounting for approximately 30% of all cancers. Although beta genus HPV are the main etiologic agents for... (Review)
Review
Keratinocyte skin cancers are the most frequent malignancy, accounting for approximately 30% of all cancers. Although beta genus HPV are the main etiologic agents for squamous cell carcinoma development in patients with epidermodysplasia verruciformis and organ transplant recipients, their role in non-melanoma skin cancer (NMSC) progression in the general population remains controversial. The aim of our review is to summarize current scientific data and to systematically analyse evidence regarding the role of HPV in keratinocyte skin cancers. A total of 2284 patients were included, of which 724 with actinic keratoses, 290 with Bowen's disease, 949 with cutaneous squamous cell carcinomas and 321 with keratoacanthomas. In the case of actinic keratoses, the majority were positive for beta (n = 372, 58.49%) and gamma HPV (n = 256, 40.25%) and only a few (n = 6, 0.94%) were positive for alpha subtypes. Similarly, most of the cutaneous squamous cell carcinomas were positive for beta (n = 248, 55.98%) and gamma HPV (n = 172, 33.82%) and 23 cases (2.42%) were positive for alpha subtypes. Bowen's disease lesions were mostly positive for beta (n = 43, 55.84%) and alpha HPV (n = 30, 38.96%), in contrast to the gamma genus (n = 4, 5.19%). Keratoacanthomas showed a high distribution among beta genus (n = 79, 50.31%) and an equal proportion between alpha (n = 39, 24.84%) and gamma (n = 39, 24.84%) genera. Studies published so far identifying HPV in keratinocyte skin cancers reflect the difference in detection methods rather than a type-specific tendency towards either actinic keratoses, Bowen's disease, squamous cell carcinoma or keratoacanthoma. On the other hand, recent evidence regarding the role of HPV vaccination in patients with non-melanoma skin cancer brings into perspective the idea of a beta-HPV vaccine or a combined alpha and beta-HPV vaccine that could be used as an adjuvant treatment measure in patients with recalcitrant non-melanoma skin cancer.
Topics: Humans; Bowen's Disease; Keratoacanthoma; Keratosis, Actinic; Papillomavirus Infections; Papillomaviridae; DNA, Viral; Skin Neoplasms; Carcinoma, Squamous Cell; Keratinocytes; Papillomavirus Vaccines
PubMed: 36000380
DOI: 10.1111/jdv.18548 -
Health Technology Assessment... Jul 2010Photodynamic therapy (PDT) is the use of a light-sensitive drug, in combination with light of a visible wavelength, to destroy target cells. PDT is used either as a... (Meta-Analysis)
Meta-Analysis Review
A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin.
BACKGROUND
Photodynamic therapy (PDT) is the use of a light-sensitive drug, in combination with light of a visible wavelength, to destroy target cells. PDT is used either as a primary treatment or as an adjunctive treatment. It is fairly well accepted in clinical practice for some types of skin cancer but has yet to be fully explored as a treatment for other forms of cancer.
OBJECTIVE
To systematically review the clinical effectiveness and safety of PDT in the treatment of Barrett's oesophagus, pre-cancerous skin conditions and the following cancers: biliary tract, brain, head and neck, lung, oesophageal and skin.
DATA SOURCES
The search strategy included searching electronic databases (between August and October 2008), followed by update searches in May 2009, along with relevant bibliographies, existing reviews, conference abstracts and contact with experts in the field.
STUDY DESIGNS
Randomised controlled trials (RCTs) in skin conditions and Barrett's oesophagus, non-randomised trials for all other sites.
PARTICIPANTS
People with Barrett's oesophagus, pre-cancerous skin conditions or primary cancer in the following sites: biliary tract, brain, head and neck, lung, oesophageal and skin.
INTERVENTION
Any type of PDT for either curative or palliative treatment.
COMPARATORS
Any comparator including differing applications of PDT treatments (relevant comparators varied according to the condition).
MAIN OUTCOMES
The outcomes measured were mortality, morbidity, quality of life, adverse events and resource use.
REVIEW METHODS
A standardised data extraction form was used. The quality of RCTs and non-randomised controlled studies was assessed using standard checklists. Data extracted from the studies were tabulated and discussed in a narrative synthesis, and the influence of study quality on results was discussed. Meta-analysis was used to estimate a summary measure of effect on relevant outcomes, with assessment of both clinical and statistical heterogeneity. Two reviewers independently screened all titles and abstracts, and data extracted and quality assessed the trials, with discrepancies resolved by discussion or referral to a third reviewer. A scoping review was also undertaken.
RESULTS
Overall, 88 trials reported in 141 publications were included, with some trials covering more than one condition. For actinic keratosis (AK), the only clear evidence of effectiveness was that PDT appeared to be superior to placebo. For Bowen's disease, better outcomes with PDT were suggested when compared with cryotherapy or fluorouracil. For basal cell carcinoma (BCC), PDT may result in similar lesion response rates to surgery or cryotherapy but with better cosmetic outcomes. For nodular lesions, PDT appeared to be superior to placebo and less effective than surgery but suggestive of better cosmetic outcome. For Barrett's oesophagus, PDT in addition to omeprazole appeared to be more effective than omeprazole alone at long-term ablation of high-grade dysplasia and slowing/preventing progression to cancer. No firm conclusions could be drawn for PDT in oesophageal cancer. Further research into the role of PDT in lung cancer is needed. For cholangiocarcinoma, PDT may improve survival when compared with stenting alone. There was limited evidence on PDT for brain cancer and cancers of the head and neck. A wide variety of photosensitisers were used and, overall, no serious adverse effects were linked to PDT.
LIMITATIONS
There were few well-conducted, adequately powered RCTs, and quality of life (QoL) and resource outcomes were under-reported. Problems were identified with reporting of key study features and quality parameters, making the reliability of some studies uncertain. Methodological limitations and gaps in the evidence base made it difficult to draw firm conclusions.
CONCLUSIONS
Evidence of effectiveness was found for PDT in the treatment of AK and nodular BCC in relation to placebo, and possibly for treating Barrett's oesophagus. However, the effectiveness of PDT in relation to other treatments is not yet apparent. High-quality trials are needed to compare PDT with relevant comparators for all meaningful outcomes, including QoL and adverse effects. Further research is also needed on patient experience of PDT, as well as on the cost-effectiveness of PDT.
Topics: Barrett Esophagus; Biliary Tract Neoplasms; Brain Neoplasms; Clinical Trials as Topic; Esophageal Neoplasms; Head and Neck Neoplasms; Humans; Lung Neoplasms; Neoplasms; Photochemotherapy; Precancerous Conditions; Quality of Life; Skin Neoplasms
PubMed: 20663420
DOI: 10.3310/hta14370 -
The Cochrane Database of Systematic... Jan 2020Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC.
OBJECTIVES
The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC.
SEARCH METHODS
We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies.
SELECTION CRITERIA
Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria.
MAIN RESULTS
One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores.
AUTHORS' CONCLUSIONS
High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.
Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Maintenance Chemotherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 31984480
DOI: 10.1002/14651858.CD012381.pub2 -
Nutrition Reviews Dec 2018Food insecurity matters for women's nutrition and health.
CONTEXT
Food insecurity matters for women's nutrition and health.
OBJECTIVE
This review sought to comprehensively evaluate how food insecurity relates to a full range of dietary outcomes (food groups, total energy, macronutrients, micronutrients, and overall dietary quality) among adult women living in Canada and the United States.
DATA SOURCES
Peer-reviewed databases (PubMed/MEDLINE, CINAHL, Scopus, Web of Science) and gray literature sources from 1995 to 2016 were searched.
DATA EXTRACTION
Observational studies were used to calculate a percentage difference in dietary intake for food-insecure and food-secure groups.
RESULTS
Of the 24 included studies, the majority found food-insecure women had lower food group frequencies (dairy, total fruits and vegetables, total grains, and meats/meat alternatives) and intakes of macro- and micronutrients relative to food-secure women. Methodological quality varied. Among high-quality studies, food insecurity was negatively associated with dairy, fruits and vegetables, grains, meats/meats alternatives, protein, total fat, calcium, iron, magnesium, vitamins A and C, and folate.
CONCLUSIONS
Results hold practical relevance for selecting nutritional targets in programs, particularly for nutrient-rich foods with iron and folate, which are more important for women's health.
Topics: Canada; Diet; Feeding Behavior; Female; Food Supply; Humans; Minerals; Nutrients; Nutritive Value; Trace Elements; United States; Vitamins; Women's Health
PubMed: 30184168
DOI: 10.1093/nutrit/nuy042 -
JAAD International Jun 2023
PubMed: 36865616
DOI: 10.1016/j.jdin.2023.01.010 -
Health Technology Assessment... Jul 2005To identify and prioritise key areas of clinical uncertainty regarding the medical management of non-ST elevation acute coronary syndrome (ACS) in current UK practice. (Review)
Review
Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.
OBJECTIVES
To identify and prioritise key areas of clinical uncertainty regarding the medical management of non-ST elevation acute coronary syndrome (ACS) in current UK practice.
DATA SOURCES
Electronic databases. Consultations with clinical advisors. Postal survey of cardiologists.
REVIEW METHODS
Potential areas of important uncertainty were identified and 'decision problems' prioritised. A systematic literature review was carried out using standard methods. The constructed decision model consisted of a short-term phase that applied the results of the systematic review and a long-term phase that included relevant information from a UK observational study to extrapolate estimated costs and effects. Sensitivity analyses were undertaken to examine the dependence of the results on baseline parameters, using alternative data sources. Expected value of information analysis was undertaken to estimate the expected value of perfect information associated with the decision problem. This provided an upper bound on the monetary value associated with additional research in the area.
RESULTS
Seven current areas of clinical uncertainty (decision problems) in the drug treatment of unstable angina patients were identified. The agents concerned were clopidogrel, low molecular weight heparin, hirudin and intravenous glycoprotein antagonists (GPAs). Twelve published clinical guidelines for unstable angina or non-ST elevation ACS were identified, but few contained recommendations about the specified decision problems. The postal survey of clinicians showed that the greatest disagreement existed for the use of small molecule GPAs, and the greatest uncertainty existed for decisions relating to the use of abciximab (a large molecule GPA). Overall, decision problems concerning the GPA class of drugs were considered to be the highest priority for further study. Selected papers describing the clinical efficacy of treatment were divided into three groups, each representing an alternative strategy. The strategy involving the use of GPAs as part of the initial medical management of all non-ST elevation ACS was the optimal choice, with an incremental cost-effectiveness ratio (ICER) of 5738 pounds per quality-adjusted life-year (QALY) compared with no use of GPAs. Stochastic analysis showed that if the health service is willing to pay 10,000 pounds per additional QALY, the probability of this strategy being cost-effective was around 82%, increasing to 95% at a threshold of 50,000 pounds per QALY. A sensitivity analysis including an additional strategy of using GPAs as part of initial medical management only in patients at particular high risk (as defined by age, ST depression or diabetes) showed that this additional strategy was yet more cost-effective, with an ICER of 3996 pounds per QALY compared with no treatment with GPA. Value of information analysis suggested that there was considerable merit in additional research to reduce the level of uncertainty in the optimal decision. At a threshold of 10,000 pounds per QALY, the maximum potential value of such research in the base case was calculated as 12.7 million pounds per annum for the UK as a whole. Taking account of the greater uncertainty in the sensitivity analyses including clopidogrel, this figure was increased to approximately 50 million pounds.
CONCLUSIONS
This study suggests the use of GPAs in all non-ST elevation ACS patients as part of their initial medical management. Sensitivity analysis showed that virtually all of the benefit could be realised by treating only high-risk patients. Further clarification of the optimum role of GPAs in the UK NHS depends on the availability of further high-quality observational and trial data. Value of information analysis derived from the model suggests that a relatively large investment in such research may be worthwhile. Further research should focus on the identification of the characteristics of patients who benefit most from GPAs as part of medical management, the comparison of GPAs with clopidogrel as an adjunct to standard care, follow-up cohort studies of the costs and outcomes of high-risk non-ST elevation ACS over several years, and exploring how clinicians' decisions combine a normative evidence-based decision model with their own personal behavioural perspective.
Topics: Acute Disease; Adrenergic beta-Antagonists; Angina, Unstable; Anticoagulants; Calcium Channel Blockers; Cost-Benefit Analysis; Decision Support Techniques; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prognosis; Quality-Adjusted Life Years; Risk Assessment; Syndrome
PubMed: 16022802
DOI: 10.3310/hta9270