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1.  Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection 
AIDS (London, England)  2014;28(6):841-849.
Despite evidence supporting antiretroviral therapy (ART) in recent HIV infection, little is known about factors that are associated with successful ART. We assessed demographic, virologic, and immunologic parameters to identify predictors of virologic response.
A 24-week observational study of ART on persons enrolled within 6 months of their estimated date of infection (EDI) evaluated baseline demographics and the collection of blood and gut specimens.
Flow cytometry analyses of blood and gut lymphocytes allowed characterization of CD4+ and CD8+ T cells at study entry and end. Additional assessments included soluble CD14 (sCD14), lipopolysaccharide, CD4+ T-cell counts, and HIV RNA levels.
Twenty nine participants initiated ART, and 17 achieved undetectable HIV RNA by study end. A longer time from EDI to ART, older age, higher sCD14, lower proportions of central memory CD4+ T cells, and higher proportions of activated CD8+ T cells were associated with detectable viremia. Multivariable logistic regression found only older age and elevated sCD14 were independently associated with persistent viremia. Additionally, we observed that ART in recent infection did not result in discernible recovery of CD4+ T cells in the gut.
In persons who started ART within 3–33 weeks from EDI, age and microbial translocation were associated with detectable HIV RNA. As observed in other cohorts, ART in recent infection did not improve proportions of total CD4+ T cells in gut-associated lymphoid tissue (GALT). This lends support to further evaluate the use of more potent ART or regimens that protect the GALT in recent HIV infection.
PMCID: PMC4049563  PMID: 24401640
antiretroviral therapy; gut-associated lymphoid tissue; microbial translocation; recent HIV; virologic response
2.  Etravirine in CSF is highly protein bound 
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
3.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
4.  HIV-associated Prospective Memory Impairment in the Laboratory Predicts Failures on a Semi-naturalistic Measure of Health Care Compliance 
The Clinical Neuropsychologist  2010;24(6):945-962.
HIV-associated neurocognitive impairment, particularly in the domain of prospective memory (ProM), increases the risk of poor everyday functioning outcomes, including medication non-adherence. However, whether ProM plays a role in health care compliance outside of the realm of medication adherence remains to be determined. This study evaluated the hypothesis that ProM is an independent predictor of failure to comply with non-medication related instructions akin to those commonly given by health care providers. Participants were 139 HIV-infected adults who underwent medical, psychiatric, and neuropsychological assessments, including a laboratory-based measure of ProM. To assess real-world compliance, participants were instructed to call the examiner 24 hours after the evaluation and report how many hours they had slept. Individuals who failed to correctly comply with these instructions (n=104) demonstrated significantly lower performance on both time- and event-based ProM at baseline than the compliant group (n=35), an effect that was primarily driven by errors of omission. ProM remained a significant predictor of noncompliance after controlling for potential confounders, including demographics (e.g., education), traditional cognitive measures of retrospective memory and executive functions, and psychiatric factors (e.g., depression). Results support the hypothesis that ProM plays a unique role in compliance with health care instructions for HIV disease management and may inform interventions designed to improve treatment outcomes.
PMCID: PMC3268682  PMID: 20661839
Episodic memory; AIDS dementia complex; compliance; adherence; everyday functioning; human immunodeficiency virus
5.  Spontaneous Strategy Use Protects Against Visual Working Memory Deficits in Older Adults Infected with HIV 
Recent studies suggest that older human immunodeficiency virus (HIV)-infected adults are at particular risk for HIV-associated neurocognitive disorders (HAND), including dementia. Deficits in attention/working memory are posited to play a central role in the development of HAND among older adults. The aim of the present study was to examine the possible protective benefits of spontaneous strategy use during a visual working memory task in 46 older and 42 younger adults infected with HIV. Results revealed a significant interaction between age and strategy use, with older adults who used a meta-cognitive strategy demonstrating superior working memory performance versus non-strategy users. This effect was not observed in the younger HIV-infected sample and was not better explained by possible confounding factors, such as education, comorbid medical conditions, or HIV disease severity. Within the older group, strategy use was associated with better executive functions and higher estimated verbal intelligence. Findings from this study suggest that working memory declines in older HIV-infected adults are moderated by the use of higher-level mnemonic strategies and may inform cognitive neurorehabilitation efforts to improve cognitive and everyday functioning outcomes in older persons living with HIV infection.
PMCID: PMC2979348  PMID: 20876195
Human immunodeficiency virus; Working memory; Aging; Strategies; Neuropsychology
6.  Is Prospective Memory a Dissociable Cognitive Function in HIV infection? 
An emerging literature indicates that HIV infection is associated with deficits in prospective memory (ProM), or the ability to execute a future intention. This literature offers evidence of neurobiological dissociability of ProM from other cognitive abilities and its incremental ecological validity as a predictor of poorer everyday functioning outcomes (e.g., medication non-adherence). The present study evaluated the hypothesis that ProM represents a unique cognitive construct in HIV disease. A confirmatory 4-factor structural equation model was tested on data derived from 162 participants with HIV. The model posited that measures of ProM comprise a unique factor, apart from standard clinical tests of retrospective memory, executive functions, and motor skills. The fit of the model was evaluated using the Bollen-Stine bootstrap method and indicated a 4-factor model with measures of ProM loading on a unique factor fit the data well, and better than a model with a single common factor hypothesized to drive cognitive performance. The results of this study lend further evidence to the dissociability of ProM in HIV infection, are consistent with prior studies in healthy adults, and contribute to a growing literature on the construct validity of ProM in HIV disease.
PMCID: PMC2912973  PMID: 20425662
Human Immunodeficiency Virus; AIDS dementia complex; Neuropsychological tests; Cognitive science; Episodic memory
7.  HIV-associated Deficits in Action (Verb) Generation May Reflect Astrocytosis 
Commensurate with the hypothesized neural dissociation between verb and noun generation, research in HIV infection shows that, relative to noun fluency, action (verb) fluency is disproportionately impaired, more strongly related to executive dysfunction, and more sensitive to declines in everyday functioning. However, whether the neurobiological correlates of HIV-associated deficits in verb and noun generation are separable have not heretofore been investigated. The present study examined the biomarker correlates of action and noun fluency in 74 participants with HIV infection. Biomarkers of viral burden, neuroaxonal damage, macrophage activation, neuroprotection, inflammation, and astrocytosis were measured in plasma and cerebrospinal fluid (CSF). Deficits in action, but not noun generation, were significantly associated with higher CSF levels of S100β, a marker of astrocyte activation, even after controlling for antiretroviral therapy, current immune compromise, and general cognitive impairment. Concurrent validity for the frontal systems hypothesis of verb generation was provided by post-hoc analyses demonstrating that S100β was also associated with measures of executive functions, but not semantic memory or psychomotor speed. Overall, these findings suggest that HIV-associated impairment in action fluency, and executive dysfunction more generally, may reflect astrocytosis (i.e., elevated S100 β). Complementing the literature in HIV and other clinical populations with frontal systems involvement, these data also support the possible neurobiological dissociation of noun and verb generation.
PMCID: PMC2878376  PMID: 19844819
Human immunodeficiency virus; cognitive processes; verbal fluency; verbs; frontal lobe
8.  The Semantic Relatedness of Cue-Intention Pairings Influences Event-Based Prospective Memory Failures in Older Adults with HIV Infection 
HIV infection and aging are each independently associated with prospective memory (ProM) impairment, which increases the risk of poor functional outcomes, including medication adherence. The incidence and prevalence of HIV infection among older adults has increased in recent years, thereby raising questions about the combined effects of these risk factors on ProM. In the present study, 118 participants were classified into four groups on the basis of HIV serostatus and age (i.e., ≤ 40 years and ≥ 50 years). Results showed significant additive effects of HIV and aging on event-based ProM, with the greatest deficits evident in the older HIV+ group, even after controlling for other demographic factors and potential medical, and psychiatric confounds. Event-based ProM impairment was particularly apparent in the older HIV+ group on trials for which the retrieval cue and intention were not semantically related. Worse performance on the semantically unrelated cue-intention trials was associated with executive dysfunction, older age, and histories of immunocompromise in the older HIV+ cohort. These data suggest that older HIV-infected adults are significantly less proficient at engaging the strategic encoding and retrieval processes required to a execute a future intention when the cue is unrelated to the intended action, perhaps secondary to greater neuropathological burden in the prefrontostriatal systems critical to optimal ProM functioning.
PMCID: PMC2854853  PMID: 19763997
Human immunodeficiency virus; Episodic memory; aging; AIDS dementia complex; multi-process theory
9.  Psychometric Characteristics of The Memory for Intentions Screening Test 
The Clinical neuropsychologist  2008;22(5):864-878.
The construct of prospective memory (ProM), or “remembering to remember,” is hypothesized to play a critical role in normal activities of daily living and has increasingly been the focus of clinical research over the past 10 years. However, the assessment of ProM as part of routine clinical care is presently hampered by the paucity of psychometrically sound, validated ProM tests available in the neuropsychological literature. The Memory for Intentions Screening Test (MIST; Raskin, 2004) is a user-friendly, comprehensive measure of ProM that demonstrates preliminary evidence of construct validity. Extending this research, this study evaluated the psychometric characteristics of the MIST in a sample of 67 healthy adults. Despite a mildly restricted range of scores, results revealed excellent inter-rater reliability, adequate split-half reliability, and satisfactory inter-relationships between the MIST summary score, subscales, and error types. Analysis of demographic correlates showed that the MIST was independently associated with both age and education, but not with sex or ethnicity. These findings broadly support the psychometric properties of the MIST, specifically its reliability and expected relationships with demographic characteristics. Recommendations are provided regarding future research to enhance the clinical usefulness of the MIST.
PMCID: PMC3057368  PMID: 18756389
reliability; test construction; neuropsychological assessment; episodic memory
10.  HIV-associated Episodic Memory Impairment: Evidence of a Possible Differential Deficit in Source Memory for Complex Visual Stimuli 
HIV infection is often associated with frontal systems pathology and related deficits in the strategic encoding and retrieval aspects of episodic memory. However, no prior HIV studies have explicitly examined source memory, which refers to recall of information regarding the context in which a declarative memory was formed. Source memory is heavily reliant upon frontal systems and strategic cognitive processes and is singly dissociable from the content of the memory (i.e., item memory), which is more dependent upon medial temporal systems and automatic processes. The present study examined item and source memory in 60 individuals with HIV infection and 35 demographically similar seronegative participants. The primary finding of interest was a significant HIV effect on source (but not item) memory for complex visual stimuli. Follow-up correlational analyses showed a significant association between visual source memory errors and impairment on measures of executive functions, working memory, and higher-level list learning encoding strategies. These findings extend the hypothesized profile of strategic encoding and retrieval deficits in HIV to the construct of source memory, which may be differentially affected relative to item memory for complex visual stimuli.
PMCID: PMC2774938  PMID: 19622690
Human immunodeficiency virus; neuropsychological assessment; encoding; episodic memory; frontal lobe
11.  Cognitive Mechanisms of Switching in HIV-Associated Category Fluency Deficits 
HIV infection is associated with deficits in category fluency, but the underlying cognitive mechanisms of such impairments have not been determined. Considering the preferential disruption of the structure and function of frontostriatal circuits in HIV disease, the present study evaluated the hypothesis that HIV-associated category fluency deficits are driven by impaired switching. Study participants were 96 HIV-infected individuals and 43 demographically comparable healthy comparison volunteers who were administered a standard measure of animal fluency and an alternating category fluency task (i.e., fruits and furniture) in a randomized order. Consistent with prior research on letter fluency, HIV infection was associated with greater impairments in switching, but not semantic clustering within the animal fluency task. Moreover, a significant interaction was observed whereby the HIV-associated deficits in switching were exacerbated by the explicit demands of the alternating fluency task. Across both fluency tasks, switching demonstrated generally small correlations with standard clinical measures of executive functions, working memory and semantic memory. Collectively, these findings suggest that HIV-associated category fluency deficits are driven by switching impairments and related cognitive abilities (e.g., mental flexibility), perhaps reflecting underlying neuropathology within prefrontostriatal networks.
PMCID: PMC2837758  PMID: 18608694
Human immunodeficiency virus; verbal fluency; nouns; cognitive processes; neuropsychological assessment
12.  Perceived confidence in the FAST exam before and after an educational intervention in a developing country 
Trauma care in developing countries suffers from many limitations related to equipment shortages, disrepair, quality assurance, and lack of training. Health care providers in the three principal hospitals in Cusco, Peru have ultrasound machines, but they do not utilize this for the focused assessment of sonography in trauma (FAST) scan (only one of the three hospitals has a computed tomography scanner).
The goal of this study was to assess the confidence of physicians in a developing country to conduct a FAST exam after an educational intervention.
Participants were Peruvian health care workers who attended a 2-day conference on trauma. Participants completed a questionnaire based on a 5-point Likert scale (1 = no confidence, 5 = high confidence) to assess comfort with the FAST scan before and after a FAST teaching workshop, which included hands-on ultrasound training. Thirteen individuals, eight of whom were physicians, completed the training and survey. Results were analyzed using paired t test statistics and are reported as pre- and post-training mean scores (± standard error), with p < 0.05 considered statistically significant.
Participants rated their confidence in using the FAST exam on a trauma patient with an average score of 3.3 (± 0.3) pre-training and 4.5 (± 0.2) post-training (p = 0.007). When asked about their comfort level in making clinical decisions based on the FAST scan, pre-training average score was 3.5 (± 0.4) and post-training was 4.5 (± 0.2), p = 0.016. Participants also answered questions about their comfort with the technical aspects of using the ultrasound machine: ability to choose the correct probe (pre: 3.9, post: 4.6, p = 0.011), choosing the correct probe orientation (pre: 3.9, post: 4.6, p = 0.008), and adjusting the depth and gain (pre: 3.1, post: 4.4, p = 0.001). Finally, participants rated their comfort with the specific views of the FAST scan: ability to find the correct subcostal view (pre: 3.3, post: 4.9, p < 0.001), right upper quadrant view (pre: 3.2, post: 4.6, p < 0.001), left upper quadrant view (pre: 3.2, post: 4.4, p = 0.001), and the pelvic view (pre: 3.2, post: 4.5, p < 0.001).
After a training session in the use of ultrasound in trauma, health care workers in Cusco, Peru reported increased confidence in their FAST scan ability and in their comfort in using this exam for clinical decision-making. Future research should include objective testing of participants’ skill as well as longitudinal follow-up to determine the extent to which the FAST scan has been incorporated into participants’ evaluations of trauma patients.
PMCID: PMC2850974  PMID: 20414382
Ultrasound; International medicine; Education
13.  Timing Is Everything: Antiretroviral Non-adherence is Associated with Impairment in Time-based Prospective Memory 
Non-adherence to combination antiretroviral therapies (cART) is highly prevalent and significantly increases the risk of adverse HIV disease outcomes. The current study evaluated the hypothesis that prospective memory – a dissociable aspect of episodic memory describing the ability to execute a future intention – plays an important role in successful cART adherence. Seventy-nine individuals with HIV infection who were prescribed at least one antiretroviral medication underwent a comprehensive neuropsychological and neuromedical evaluation prior to completing a one-month observation of their cART adherence as measured by electronic medication monitoring. Non-adherent individuals (n = 31) demonstrated significantly poorer prospective memory functioning as compared to adherent persons (n = 48), particularly on an index of time-based ProM (i.e., elevated loss of time errors). Deficits in time-based prospective memory were independently predictive of cART non-adherence, even after considering the possible influence of established predictors of adherence, such as general cognitive impairment (e.g., retrospective learning and memory) and psychiatric comorbidity (e.g., depression). These findings extend a nascent literature showing that impairment in time-based prospective memory significantly increases the risk of medication non-adherence and therefore may guide the development of novel strategies for intervention.
PMCID: PMC2776623  PMID: 19128527
Human immunodeficiency virus; AIDS dementia complex; Neuropsychological tests; Cognitive science; Patient compliance; Time perception
14.  Prospective Memory in HIV Infection: Is “Remembering to Remember” a Unique Predictor of Self-reported Medication Management? 
Optimal adherence to antiretroviral medications is critical to the effective long-term management of HIV infection. Although prospective memory (ProM; i.e., “remembering to remember”) has long been theorized to play an important role in medication adherence, no prior studies have evaluated whether HIV-associated ProM impairment possesses unique predictive value in this regard. Results from this study demonstrate a robust association between ProM impairment and self-reported medication management in 87 HIV-infected persons currently prescribed antiretroviral medications. Specifically, more frequent ProM complaints and performance deficits on both laboratory and semi-naturalistic ProM tasks were all independently related to poorer self-reported medication management. A series of hierarchical regression analyses revealed that HIV-associated ProM impairment accounted for a significant amount of variance in self-reported medication management beyond that which was explained by other factors known to predict nonadherence, including mood disorders, psychosocial variables, environmental structure, and deficits on a traditional battery of neuropsychological tests. Overall, these findings support the hypothesis that ProM captures a unique and largely untapped aspect of cognition that is germane to optimal medication adherence. The potential benefits of individualized remediation strategies that are informed by conceptual models of ProM and specifically target medication adherence warrant further exploration.
PMCID: PMC2408931  PMID: 18243645
Human immunodeficiency virus; Neuropsychological assessment; Episodic memory; Treatment compliance
15.  HIV-associated Prospective Memory Impairment Increases Risk of Dependence in Everyday Functioning 
Neuropsychology  2008;22(1):110-117.
HIV infection is associated with impairments in prospective memory (ProM), an aspect of episodic memory that refers to the ability to execute a future intention, such as remembering to take a medication at a specific time. The current study sought to examine the relationship between HIV-associated ProM impairment and the successful management of independent activities of daily living (IADLs). In a cohort of 66 HIV-infected individuals, ProM accounted for a significant proportion of variance in self-reported IADL dependence over and above that which was explained by retrospective memory and current affective distress. Analysis of component cognitive processes revealed that the relationship between HIV-associated ProM deficits and IADL dependence was driven by impaired cue detection and self-initiated intention retrieval. Results were not better explained by demographic factors, HIV disease severity, psychiatric comorbidity, or substance use. Collectively, these data support the potential incremental ecological validity of ProM as a predictor of dependence in IADLs among persons living with HIV infection.
PMCID: PMC2249562  PMID: 18211160
Human immunodeficiency virus; neuropsychological assessment; episodic memory; activities of daily living
16.  Frequency and predictors of self-reported prospective memory complaints in individuals infected with HIV 
Failures of episodic retrospective memory (RetM) are among the most frequently reported cognitive complaints endorsed by individuals living with HIV infection. The present study sought to examine the nature, frequency, and determinants of self-reported complaints of prospective memory (ProM) in HIV, which is a singly dissociable and ecologically relevant aspect of episodic memory involving the execution of future intentions. Seventy-five HIV seropositive individuals and 60 seronegative volunteers were administered the Prospective and Retrospective Memory Questionnaire (PMRQ) as part of extensive neuropsychological, psychiatric, and medical research assessments. The HIV sample endorsed more frequent ProM complaints in daily life than the seronegative group, particularly on items requiring self-initiated cue detection and retrieval. Within both study groups, ProM complaints were significantly more frequent than RetM complaints. Although the HIV sample was impaired relative to the seronegative group on an objective, performance-based ProM test, self-reported ProM complaints did not correspond to actual ProM abilities. However, greater frequency of self-reported ProM complaints was moderately associated with increased fatigue, as well as with symptoms of anxiety and depression. Consistent with prior research on RetM in HIV, results indicate that affective distress contributes to a metamemory deficit for HIV-associated ProM impairment, which highlights the potential importance of assessing both self-reported and performance-based ProM in clinical and research neuroAIDS evaluations.
PMCID: PMC1851919  PMID: 17289343
Human immunodeficiency virus; Neuropsychological assessment; Self-report; Fatigue; Episodic memory; Metacognition
17.  Deficits in Cue Detection and Intention Retrieval Underlie Prospective Memory Impairment in Schizophrenia 
Schizophrenia research  2006;90(1-3):344-350.
Emerging evidence indicates that individuals with schizophrenia (SCZ) may exhibit deficits in prospective memory (ProM), a dissociable and ecologically important aspect of episodic memory entailing the formation, maintenance, and execution of future intentions. The present study aimed to elucidate the component processes of ProM impairment in 41 individuals with SCZ relative to 41 demographically similar healthy comparison (HC) participants. Results revealed that the SCZ group performed worse than HCs on overall ProM, with comparable deficits on time- and event-based ProM trials. In the SCZ cohort, better ProM performance was associated with younger age and less severe negative symptoms. Although a significantly greater number of task substitution and loss of time errors were evident in the SCZ group as compared to HCs, the most prevalent error type in SCZ was characterized by a complete failure to respond to the ProM cue. Importantly, the SCZ and HC groups did not differ on a post-test multiple-choice recognition trial, suggesting adequate formation and maintenance (i.e., retention) of the ProM cue-intention pairing when self-directed monitoring and retrieval demands were minimized. Findings indicate that SCZ is associated with impairment in the cue detection and self-initiated retrieval components of executing future intentions, which is consistent with a possible prefrontostriatal loop neuropathogenesis. Further studies are needed to explore the neurobiological mechanisms of SCZ-associated ProM impairment and the impact of such deficits on daily functioning (e.g., medication compliance).
PMCID: PMC1851918  PMID: 17175138
Schizophrenia; neuropsychological assessment; cognitive processes; episodic memory

Results 1-17 (17)