A systematic review and network meta-analysis of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

BACKGROUND: Various treatments for acne vulgaris exist, but little is known about their comparative effectiveness in relation to acne severity. OBJECTIVES: To identify best treatments for mild-to-moderate and moderate-to-severe acne, as determined by clinician-assessed morphological features. METHODS: We undertook a systematic review and network meta-analysis of randomized controlled trials (RCTs) assessing topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, published up to May 2020. Outcomes included percentage change in total lesion count from baseline, treatment discontinuation for any reason, and discontinuation owing to side-effects. Risk of bias was assessed using the Cochrane risk-of-bias tool and bias adjustment models. Effects for treatments with ≥ 50 observations each compared with placebo are reported below. RESULTS: We included 179 RCTs with approximately 35 000 observations across 49 treatment classes. For mild-to-moderate acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with benzoyl peroxide (BPO) [mean difference 26·16%, 95% credible interval (CrI) 16·75-35·36%]; physical - chemical peels, e.g. salicylic or mandelic acid (39·70%, 95% CrI 12·54-66·78%) and photochemical therapy (combined blue/red light) (35·36%, 95% CrI 17·75-53·08%). Oral pharmacological treatments (e.g. antibiotics, hormonal contraceptives) did not appear to be effective after bias adjustment. BPO and topical retinoids were less well tolerated than placebo. For moderate-to-severe acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with lincosamide (clindamycin) (44·43%, 95% CrI 29·20-60·02%); oral pharmacological - isotretinoin of total cumulative dose ≥ 120 mg kg-1 per single course (58·09%, 95% CrI 36·99-79·29%); physical - photodynamic therapy (light therapy enhanced by a photosensitizing chemical) (40·45%, 95% CrI 26·17-54·11%); combined - BPO with topical retinoid and oral tetracycline (43·53%, 95% CrI 29·49-57·70%). Topical retinoids and oral tetracyclines were less well tolerated than placebo. The quality of included RCTs was moderate to very low, with evidence of inconsistency between direct and indirect evidence. Uncertainty in findings was high, in particular for chemical peels, photochemical therapy and photodynamic therapy. However, conclusions were robust to potential bias in the evidence. CONCLUSIONS: Topical pharmacological treatment combinations, chemical peels and photochemical therapy were most effective for mild-to-moderate acne. Topical pharmacological treatment combinations, oral antibiotics combined with topical pharmacological treatments, oral isotretinoin and photodynamic therapy were most effective for moderate-to-severe acne. Further research is warranted for chemical peels, photochemical therapy and photodynamic therapy for which evidence was more limited. What is already known about this topic? Acne vulgaris is the eighth most common disease globally. Several topical, oral, physical and combined treatments for acne vulgaris exist. Network meta-analysis (NMA) synthesizes direct and indirect evidence and allows simultaneous inference for all treatments forming an evidence network. Previous NMAs have assessed a limited range of treatments for acne vulgaris and have not evaluated effectiveness of treatments for moderate-to-severe acne. What does this study add? For mild-to-moderate acne, topical treatment combinations, chemical peels, and photochemical therapy (combined blue/red light; blue light) are most effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy (light therapy enhanced by a photosensitizing chemical) are most effective. Based on these findings, along with further clinical and cost-effectiveness considerations, National Institute for Health and Care Excellence (NICE) guidance recommends, as first-line treatments, fixed topical treatment combinations for mild-to-moderate acne and fixed topical treatment combinations, or oral tetracyclines combined with topical treatments, for moderate-to-severe acne.

Cost-effectiveness of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

BACKGROUND: Acne vulgaris is a common skin condition that may cause psychosocial distress. There is evidence that topical treatment combinations, chemical peels and photochemical therapy (combined blue/red light) are effective for mild-to-moderate acne, while topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy are most effective for moderate-to-severe acne. Effective treatments have varying costs. The National Institute for Health and Care Excellence (NICE) in England considers cost-effectiveness when producing national clinical, public health and social care guidance. AIM: To assess the cost-effectiveness of treatments for mild-to-moderate and moderate-to-severe acne to inform relevant NICE guidance. METHODS: A decision-analytical model compared costs and quality-adjusted life-years (QALYs) of effective topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, from the perspective of the National Health Service in England. Effectiveness data were derived from a network meta-analysis. Other model input parameters were based on published sources, supplemented by expert opinion. RESULTS: All of the assessed treatments were more cost-effective than treatment with placebo (general practitioner visits without active treatment). For mild-to-moderate acne, topical treatment combinations and photochemical therapy (combined blue/red light) were most cost-effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, and oral isotretinoin were the most cost-effective. Results showed uncertainty, as reflected in the wide confidence intervals around mean treatment rankings. CONCLUSION: A range of treatments are cost-effective for the management of acne. Well-conducted studies are needed to examine the long-term clinical efficacy and cost-effectiveness of the full range of acne treatments.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer.

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs. Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed. Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention. Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated. Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs. Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

CMIP and ATP2C2 modulate phonological short-term memory in language impairment.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

Pharmacological agents for developmental stuttering in children and adolescents: a systematic review.

Stuttering affects approximately 5% of children up to the teenage years. There are many possible forms of intervention, one of which is pharmacotherapy. No review about the treatment of stuttering with pharmacological agents in children and adolescents has been undertaken. The objectives of this review were to determine the extent of previous research in this area and to assess the success of pharmacological agents in reducing the frequency of disfluency in child and adolescent stutterers (<18 years). A systematic search of MEDLINE, PsychInfo, Embase, and Cochrane Systematic Review databases was carried out to identify potential studies for the review. Studies that met specified criteria were selected for detailed examination, and the quality of evidence they provided was assessed according to 7 criteria that pertained to study design and data provision. Seven publications met the inclusion criteria for the review. Only 1 publication was classified as strong evidence quality, and this reported that clonidine did not reduce the frequency of disfluency in a group of 25 individuals who stuttered. All further publications were classified as either very low or low evidence quality. The agents examined were risperidone, olanzapine, clonidine, tiapride, haloperidol, and chlorpromazine.

Impairment in non-word repetition: a marker for language impairment or reading impairment?

AIM: A deficit in non-word repetition (NWR), a measure of short-term phonological memory proposed as a marker for language impairment, is found not only in language impairment but also in reading impairment. We evaluated the strength of association between language impairment and reading impairment in children with current, past, and no language impairment and assessed any differential impairment of NWR, compared with two other tests of verbal memory in children with language impairment with and without reading impairment. METHOD: Our sample comprised children aged 6-16y 11mo participating in a study of the genetics of language impairment: 78 children from 68 families (53 males, 25 females) with current language impairment (C-LI), compared with their 74 siblings: 25 children (18 males, seven females) with a past history of language impairment and 49 children (27 males, 22 females) who had never had a language impairment. The tests used were the Clinical Evaluation of Language Fundamentals (CELF III), the Children's Test of Non-word Repetition (CN-Rep), the Wide Range Assessment of Memory and Learning (WRAML) verbal memory index, the Wechsler Intelligence Scale for Children-III (WISC-III) digit span, and the Wechsler Objective Reading Dimensions (WORD(UK) ). RESULTS: Reading impairment was present in two-thirds of the children with current language impairment. NWR deficits were significantly worse in children with language impairment who had reading impairment in reading decoding (p=0.007 and 0.004 - average group compared with borderline and definitely impaired groups respectively) or spelling (p=0.002 and 0.005 - average group compared with borderline and severely impaired groups respectively) (not correlated with severity of language impairment) but not comprehension impairment. In contrast, WISC digit span and WRAML verbal memory were impaired in all children with language impairment and did not differentiate those who also had reading impairment. INTERPRETATION: We suggest that current NWR ability may be a marker of a process specifically underlying language impairment, co-occurring with reading impairment involving reading decoding and spelling, rather than a generic correlate of language impairment. Other verbal memory deficits appear to be pervasive in children with language impairment.

Memory impairment in children with language impairment.

AIM: The aim of this study was to assess whether any memory impairment co-occurring with language impairment is global, affecting both verbal and visual domains, or domain specific. METHOD: Visual and verbal memory, learning, and processing speed were assessed in children aged 6 years to 16 years 11 months (mean 9 y 9 m, SD 2 y 6 mo) with current, resolved, and no language impairment using the Wide Range Assessment of Memory and Learning (WRAML), a standardized memory and learning test for children, and the Children's Test of Non-Word Repetition (CNRep), a test of phonological short-term memory. Fifty-one children (38 males, 13 females) with current speech and language impairment from 49 families were compared with 13 siblings (11 males, 2 females) with a past history of language impairment and 26 (15 males, 11 females) who had never had language impairment. RESULTS: Children with current language impairment showed impairment in all verbal memory measures compared with children who had never had language impairment, and these impairments were still evident in children with a past history of learning impairment. Visual memory and learning were not impaired compared with children who had never had language impairment. The severity of verbal memory impairment correlated with the degree of language impairment. INTERPRETATION: We concluded that in language impairment there is domain specificity of memory impairment affecting verbal processing.

Exploring the relation between prenatal and neonatal complications and later autistic-like features in a representative community sample of twins.

Prenatal and neonatal events were reported by parents of 13,690 eighteen-month-old twins enrolled in the Twins Early Development Study, a representative community sample born in England and Wales. At ages 7-8, parents and teachers completed questionnaires on social and nonsocial autistic-like features and parents completed the Childhood Asperger Syndrome Test. Correlations between prenatal and neonatal events and autistic-like features were weak, both in the whole sample (r = .00-.07) and at the 5% quantitative extreme (phenotypic group correlations = .01-.11), after controlling for socioeconomic status and cognitive ability. Neonatal problems showed modest heritability (13%-14%) and significant shared and nonshared environmental influences (55%-59% and 28%-31%, respectively). Differences in identical twins' neonatal problems correlated weakly with their difference scores on autistic-like features (r = .01-.06).

Genetic etiology in cases of recovered and persistent stuttering in an unselected, longitudinal sample of young twins.

PURPOSE: The contribution of genetic factors in the persistence of and early recovery from stuttering was assessed. METHOD: Data from the Twins Early Development Study were employed. Parental reports regarding stuttering were collected at ages 2, 3, 4, and 7 years, and were used to classify speakers into recovered and persistent groups. Of 12,892 children with at least 2 ratings, 950 children had recovered and 135 persisted in their stutter. RESULTS: Logistic regressions showed that the rating at age 2 was not predictive of later stuttering, whereas ratings at ages 3 and 4 were. Concordance rates were consistently higher for monozygotic than for dizygotic twin pairs (with the exception of girls at age 3). At 3, 4, and 7 years, the liability to stuttering was highly heritable (h2 estimates of between .58 and .66). Heritability for the recovered and persistent groups was also high but did not differ from each other. CONCLUSION: Stuttering appears to be a disorder that has high heritability and little shared environment effect in early childhood and for recovered and persistent groups of children, by age 7. The clinical implications of the findings are discussed.

Grammatical gender effects on cognition: implications for language learning and language use.

In 4 experiments, the authors addressed the mechanisms by which grammatical gender (in Italian and German) may come to affect meaning. In Experiments 1 (similarity judgments) and 2 (semantic substitution errors), the authors found Italian gender effects for animals but not for artifacts; Experiment 3 revealed no comparable effects in German. These results suggest that gender effects arise as a generalization from an established association between gender of nouns and sex of human referents, extending to nouns referring to sexuated entities. Across languages, such effects are found when the language allows for easy mapping between gender of nouns and sex of human referents (Italian) but not when the mapping is less transparent (German). A final experiment provided further constraints: These effects during processing arise at a lexical-semantic level rather than at a conceptual level.

Stroke rehabilitation: long-term rehabilitation after stroke.

Many stroke survivors, despite improvements in mortality and morbidity, remain dependent on others for everyday activities. People with stroke need access to effective specialist multidisciplinary rehabilitation services that are organised and integrated within the whole system of health and social care. They also commonly come under the care of generalists in various clinical contexts, including intercurrent illness. This Clinical Medicine Concise Guideline abstracts key recommendations from the National Institute for Health and Care Excellence Clinical Guideline 162 on stroke rehabilitation of particular relevance to clinicians in general medicine, to inform their front-line practice and promote liaison and collaboration with the specialist service.

The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting.

OBJECTIVES: To determine and compare the diagnostic accuracy of serum natriuretic peptide levels (B type natriuretic peptide, N terminal probrain natriuretic peptide (NTproBNP), and mid-regional proatrial natriuretic peptide (MRproANP)) in people presenting with acute heart failure to acute care settings using thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure. DESIGN: Systematic review and diagnostic meta-analysis. DATA SOURCES: Medline, Embase, Cochrane central register of controlled trials, Cochrane database of systematic reviews, database of abstracts of reviews of effects, NHS economic evaluation database, and Health Technology Assessment up to 28 January 2014, using combinations of subject headings and terms relating to heart failure and natriuretic peptides. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible studies evaluated one or more natriuretic peptides (B type natriuretic peptide, NTproBNP, or MRproANP) in the diagnosis of acute heart failure against an acceptable reference standard in consecutive or randomly selected adults in an acute care setting. Studies were excluded if they did not present sufficient data to extract or calculate true positives, false positives, false negatives, and true negatives, or report age independent natriuretic peptide thresholds. Studies not available in English were also excluded. RESULTS: 37 unique study cohorts described in 42 study reports were included, with a total of 48 test evaluations reporting 15 263 test results. At the lower recommended thresholds of 100 ng/L for B type natriuretic peptide and 300 ng/L for NTproBNP, the natriuretic peptides have sensitivities of 0.95 (95% confidence interval 0.93 to 0.96) and 0.99 (0.97 to 1.00) and negative predictive values of 0.94 (0.90 to 0.96) and 0.98 (0.89 to 1.0), respectively, for a diagnosis of acute heart failure. At the lower recommended threshold of 120 pmol/L, MRproANP has a sensitivity ranging from 0.95 (range 0.90-0.98) to 0.97 (0.95-0.98) and a negative predictive value ranging from 0.90 (0.80-0.96) to 0.97 (0.96-0.98). At higher thresholds the sensitivity declined progressively and specificity remained variable across the range of values. There was no statistically significant difference in diagnostic accuracy between plasma B type natriuretic peptide and NTproBNP. CONCLUSIONS: At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure. Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required. There is no statistical difference between the diagnostic accuracy of plasma B type natriuretic peptide and NTproBNP. Introduction of natriuretic peptide measurement in the investigation of patients with suspected acute heart failure has the potential to allow rapid and accurate exclusion of the diagnosis.

Predicting stuttering from phonetic complexity in German.

UNLABELLED: This study investigated how phonetic complexity affects stuttering rate in German and how this changes developmentally. Phonetic difficulty was assessed using Jakielski's index [Motor Organization in the Acquisition of Consonant Clusters, Dissertation/Ph.D. Thesis, University of Texas Austin, 1998] of phonetic complexity (IPC) in which words are scored on eight different characteristics. Stuttering rate was not related to IPC score for German function words, as previously shown for Spanish and English. Significant correlations between stuttering rate and IPC score were found for content words for children over the age of six and adults. It was also found that German content words have a higher mean IPC sum compared to their English counterparts. There was a bigger difference in IPC score between fluent and stuttered words in German than in English. Factor 5 (word shape) influenced stuttering rates in both German age groups. This has also been found for Spanish but does not apply to English. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe a method to measure phonetic complexity and how this affects stuttering rates for words of different grammatical classes; (2) explain why this method is suitable for different languages and age groups; (3) detect which phonetic characteristics have most impact on different age groups in English and German; (4) assess possible theoretical reasons for these findings.

Predicting stuttering from linguistic factors for German speakers in two age groups.

UNLABELLED: Brown's factors [J. Speech Disorders 10 (1945) 181] predict the likely loci of disfluency in English-speaking adults who stutter. A word is more likely to be stuttered for these speakers if it is a content word, starts with a consonant, is positioned at the beginning of a sentence, and if it is a long word. These same factors were examined in native German-speaking children and adults who stutter. Speech data of 15 German adults and 17 children were coded according to Brown's factors. For the adult group, it was predicted that words starting with consonants would not lead to as much of an increase in disfluencies compared with English samples, because of cross-linguistic differences in syllable onset properties. It was predicted that stuttering would be more likely in later sentence positions in German because in German the verb is usually near the end of a sentence. There were no obvious reasons to expect differences on the two remaining factors, content words and word length. With children, it was hypothesised that Brown's factors that specify level of linguistic difficulty would not be such a good predictor of stuttering rate. Specifically, it was predicted that the difference in stuttering rate between function and content words would be lower in children. For the adults both word type (content/function) and word length increased stuttering rate significantly, whereas changes in stuttering rate for the other two factors were non-significant. It was also found that when word difficulty (based on a combined measure of all factors) increased, stuttering rate rose. With children, only the word-length factor was significant, and stuttering rate was not governed to the same extent by overall word difficulty. Conclusions are drawn as to the effect of linguistic and motor influences on stuttering. EDUCATIONAL OBJECTIVES: The reader will learn about and be able to describe: (1) how linguistic factors affect stuttering rates in German; (2) the different patterns of adults and children who stutter and how language might influence this pattern; and (3) how to interpret these findings in light of a current theory of fluency failure.