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1.  Prospective Memory in HIV-1 Infection 
The cognitive deficits associated with HIV-1 infection are thought to primarily reflect neuropathophysiology within the fronto-striato-thalamo-cortical circuits. Prospective memory (ProM) is a cognitive function that is largely dependent on prefronto-striatal circuits, but has not previously been examined in an HIV-1 sample. A form of episodic memory, ProM involves the complex processes of forming, monitoring, and executing future intentions vis-à-vis ongoing distractions. The current study examined ProM in 42 participants with HIV-1 infection and 29 demographically similar seronegative healthy comparison (HC) subjects. The HIV-1 sample demonstrated deficits in time-and event-based ProM, as well as more frequent 24-hour delay ProM failures and task substitution errors relative to the HC group. In contrast, there were no significant differences in recognition performance, indicating that the HIV-1 group was able to accurately retain and recognize the ProM intention when retrieval demands were minimized. Secondary analyses revealed that ProM performance correlated with validated clinical measures of executive functions, episodic memory (free recall), and verbal working memory, but not with tests of semantic memory, retention, or recognition discrimination. Taken together, these findings indicate that HIV-1 infection is associated with ProM impairment that is primarily driven by a breakdown in the strategic (i.e., executive) aspects of retrieving future intentions, which is consistent with a prefronto-striatal circuit neuropathogenesis.
doi:10.1080/13803390590949494
PMCID: PMC1853378  PMID: 16676475
2.  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.
doi:10.1080/13803390903130737
PMCID: PMC2854853  PMID: 19763997
Human immunodeficiency virus; Episodic memory; aging; AIDS dementia complex; multi-process theory
3.  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.
doi:10.1016/j.acn.2006.12.006
PMCID: PMC1851919  PMID: 17289343
Human immunodeficiency virus; Neuropsychological assessment; Self-report; Fatigue; Episodic memory; Metacognition
4.  Transparent Meta-Analysis: Does Aging Spare Prospective Memory with Focal vs. Non-Focal Cues? 
PLoS ONE  2011;6(2):e16618.
Background
Prospective memory (ProM) is the ability to become aware of a previously-formed plan at the right time and place. For over twenty years, researchers have been debating whether prospective memory declines with aging or whether it is spared by aging and, most recently, whether aging spares prospective memory with focal vs. non-focal cues. Two recent meta-analyses examining these claims did not include all relevant studies and ignored prevalent ceiling effects, age confounds, and did not distinguish between prospective memory subdomains (e.g., ProM proper, vigilance, habitual ProM) (see Uttl, 2008, PLoS ONE). The present meta-analysis focuses on the following questions: Does prospective memory decline with aging? Does prospective memory with focal vs. non-focal cues decline with aging? Does the size of age-related declines with focal vs. non-focal cues vary across ProM subdomains? And are age-related declines in ProM smaller than age-related declines in retrospective memory?
Methods and Findings
A meta-analysis of event-cued ProM using data visualization and modeling, robust count methods, and conventional meta-analysis techniques revealed that first, the size of age-related declines in ProM with both focal and non-focal cues are large. Second, age-related declines in ProM with focal cues are larger in ProM proper and smaller in vigilance. Third, age-related declines in ProM proper with focal cues are as large as age-related declines in recall measures of retrospective memory.
Conclusions
The results are consistent with Craik's (1983) proposal that age-related declines on ProM tasks are generally large, support the distinction between ProM proper vs. vigilance, and directly contradict widespread claims that ProM, with or without focal cues, is spared by aging.
doi:10.1371/journal.pone.0016618
PMCID: PMC3033399  PMID: 21304905
5.  Prospective Memory Deficits in Ecstasy Users: Effects of Longer Ongoing Task Delay Interval 
Ecstasy use has been associated with neurotoxicity and neurocognitive impairment in a variety of domains, including prospective memory (ProM), which involves the delayed execution of a previously encoded intention in response to a specific cue. The present study adopted the multiprocess theory of ProM to evaluate the hypothesis that ecstasy users would evidence differentially impaired ProM on longer versus shorter ongoing task delays. Ecstasy (n = 31) users, high-risk alcohol users (n = 21) and healthy nonusers (n = 31) completed the short (2-min) and long (15-min) delay ProM scales of the Memory for Intentions Screening Test. Results showed a significant group by ProM delay interaction, such that ecstasy users performed comparably to the comparison groups on short-delay trials, but were impaired on long-delay ProM, particularly for time-based cues. Among the ecstasy users, long-delay ProM was positively associated with risky decision-making, but not with retrospective memory or other aspects of executive functions. These findings suggest that ecstasy users may be particularly susceptible to deficits in strategic target monitoring and maintenance of cue-intention pairings over longer ProM delays. Findings are discussed in the context of their potential everyday functioning (e.g., academic, vocational) and treatment implications for ecstasy users.
doi:10.1080/13803395.2011.614595
PMCID: PMC3229681  PMID: 22047194
Prospective memory; ecstasy; substance abuse; episodic memory; executive functions; time perception; cognition
6.  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).
doi:10.1016/j.schres.2006.11.005
PMCID: PMC1851918  PMID: 17175138
Schizophrenia; neuropsychological assessment; cognitive processes; episodic memory
7.  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.
doi:10.1080/13854046.2010.501343
PMCID: PMC3268682  PMID: 20661839
Episodic memory; AIDS dementia complex; compliance; adherence; everyday functioning; human immunodeficiency virus
8.  Neuropsychological Substrates and Everyday Functioning Implications of Prospective Memory Impairment in Schizophrenia 
Schizophrenia research  2007;106(1):42-49.
Individuals with schizophrenia demonstrate impairment in prospective memory (ProM), which describes the multifaceted ability to execute a future intention. Despite its clear implications for everyday functioning, the neuropsychological substrates and functional correlates of ProM impairment in schizophrenia remain poorly understood. In this study, the Memory for Intentions Screening Test (MIST), a standardized measure of ProM, was administered to 72 outpatients with schizophrenia or schizoaffective disorder as part of a comprehensive neuropsychological and psychiatric research evaluation. Results showed that ProM was positively correlated with standard clinical tests of attention, working memory, processing speed, learning, and executive functioning, but not delayed recall. In the context of multiple neuropsychological predictors, learning ability was the only domain that independently contributed to ProM. Importantly, better ProM was predictive of higher functional capacity (as measured by the UCSD Performance-Based Skills Assessment—Brief Version), above and beyond the variability explained by demographic and disease factors. Analysis of component processes revealed that event-based ProM, as well as no response (i.e., omission) and task substitution errors were the strongest predictors of everyday functioning. Overall, these findings suggest that ProM impairment in schizophrenia is associated with multiple cognitive substrates, particularly episodic learning deficits, and plays an important role in everyday living skills. Studies regarding the potential effectiveness of ProM-based remediation strategies to improve functional outcomes in schizophrenia are indicated.
doi:10.1016/j.schres.2007.10.030
PMCID: PMC2576491  PMID: 18055178
learning; cognition; psychotic disorders
9.  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.
doi:10.1016/j.acn.2007.12.006
PMCID: PMC2408931  PMID: 18243645
Human immunodeficiency virus; Neuropsychological assessment; Episodic memory; Treatment compliance
10.  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.
doi:10.1037/0894-4105.22.1.110
PMCID: PMC2249562  PMID: 18211160
Human immunodeficiency virus; neuropsychological assessment; episodic memory; activities of daily living
11.  Misremembering Future Intentions in Methamphetamine Dependent Individuals 
The Clinical Neuropsychologist  2011;25(2):269-286.
Methamphetamine (MA) dependence is associated with neural abnormalities (e.g., frontal systems neurotoxicity) and corresponding cognitive deficits, including impairment in episodic memory and executive functions. This study evaluated the hypothesis that MA use is associated with impairment in memory for intentions, or prospective memory (ProM), which is an ecologically relevant aspect of episodic memory that involves the execution of a previously encoded intention at an appropriate moment in the future and is known to rely on frontal systems integrity. Thirty-nine MA-dependent individuals and 26 demographically similar non-MA-using comparison subjects were administered the Memory for Intentions Screening Test (MIST). The MA group performed significantly lower than the comparison participants on overall ProM, an effect that could not be better explained by demographics, psychiatric factors, infectious disease comorbidity, or other substance use disorders. The ProM impairment observed in the MA group was comparable on time- and event-based tasks and was marked by an increased rate of task substitution (i.e., intrusions) and loss of time (e.g., early responding) errors. Within the MA cohort, ProM impairment was associated with executive dysfunction and earlier age at first MA use. Findings suggest that individuals with MA dependence experience difficulty in the strategic components involved in the retrieval of future intentions and are discussed with regard to their implications for everyday functioning.
doi:10.1080/13854046.2010.546812
PMCID: PMC3264429  PMID: 21331980
Prospective memory; methamphetamine; episodic memory; executive functions; time perception; cognition
12.  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.
doi:10.1080/13803391003596470
PMCID: PMC2912973  PMID: 20425662
Human Immunodeficiency Virus; AIDS dementia complex; Neuropsychological tests; Cognitive science; Episodic memory
13.  Markers of Macrophage Activation and Axonal Injury are Associated With Prospective Memory in HIV-1 Disease 
Objective
To use clinical specimens to better understand the neuropathogenesis of prospective memory (ProM) functioning in persons with HIV-1 infection.
Background
Emergent evidence suggests that HIV-1 is associated with impaired ProM, but the underlying neuropathophysiology of this deficit is not known.
Methods
Thirty-five nondemented subjects with HIV-1 infection completed measures of both ProM (ie, memory for future intentions) and retrospective memory (RM; ie, memory for past episodes). A panel of biomarkers reflecting several possible neuropathogenic mechanisms of HIV was measured in plasma and cerebrospinal fluid, including HIV-1 RNA, total tau, monocyte chemoattractant protein-1 (MCP-1), soluble receptor for tumor necrosis factor type II, and fibroblast growth factor 1.
Results
After controlling for antiretroviral therapy and CD4 lymphocyte count, higher levels of MCP-1 in plasma, and soluble receptor for tumor necrosis factor type II and tau in cerebrospinal fluid were associated with ProM, but not RM. Markers of astrocytosis, growth factor depletion, and HIV-1 replication did not predict either ProM or RM.
Conclusions
ProM impairment in HIV-1 may be dissociable from RM, perhaps reflecting specific neuropathogenic mechanisms of macrophage activation and axonal injury.
doi:10.1097/01.wnn.0000213916.10514.57
PMCID: PMC1939824  PMID: 17159619
neuropsychology; HIV; memory; neuropathogenesis; biomarkers
14.  Comparative analysis of Erk phosphorylation suggests a mixed strategy for measuring phospho-form distributions 
Comparative analysis of Erk phosphorylation suggests a mixed strategy for measuring phospho-form distributions. Four methods were compared for quantifying the proportion of Erk2 ‘phospho-forms' in differentially phosphorylated samples, revealing excellent agreement between mass spectrometry and nuclear magnetic resonance, but significant discrepancies with western blots.
We compared four methods for quantifying the proportions of phospho-forms, or ‘phospho-form distribution', of a multiply phosphorylated protein, using as an example the MAP kinase Erk2, with two principal phosphorylation sites.Measurements by mass spectrometry (MS) and by nuclear magnetic resonance (NMR) agreed to within 10%, but phospho-specific antibody measurements exhibited semi-quantitative discrepancies with these, sometimes suggesting reverse trends to those found by the biophysical methods.NMR revealed under our conditions that Erk was phosphorylated on four, not two, sites.A combination of peptide-based MS and protein-based MS provided an optimum strategy for determining the 16=24 member phospho-form distribution.
Protein post-translational modification is one of the most significant regulatory mechanisms in cellular physiology, and protein phosphorylation is the most widely studied of these. An individual molecule may be phosphorylatable on multiple residues, allowing it to exist in a multiplicity of combinatorial patterns of modification; with n-sites, there may be 2n such ‘phospho-forms'. Recent work on many distinct types of proteins—ion channels, signalling enzymes, transcription factors, co-activators, circadian clock components—has shown that different phospho-forms may have different downstream effects. The impact of multisite phosphorylation, therefore, is determined by the proportions of the various phospho-forms that are present in the molecular population of the given protein. This ‘phospho-form distribution' is dynamically and collectively regulated by the opposing actions of the relevant kinases and phosphatases. This presents a more challenging perspective than is depicted in the typical cartoon diagram, in which is shown only a single phospho-form, usually the maximally phosphorylated one, and the underlying dynamics of modification and demodification is left implicit.
The present paper sets out to bring this perspective of phospho-forms and phospho-form distributions to a wider biological audience, to compare current methods for measuring them and to discuss the challenges in developing a general strategy applicable to the kinds of proteins typically found in cellular physiology. We chose to analyse the 42 kDa mitogen-activated protein (MAP) kinase Erk2 (Erk). Erk is a paradigmatic signalling protein that is phosphorylated on T and Y residues in a TEY motif within its kinase-activation loop. Because these sites are so close together, multiple methods may be used to detect phospho-forms and we compared four: western blots with phospho-specific antibodies; peptide-based liquid chromatography (LC)/mass spectrometry (MS), in which proteins are first digested into peptide (pepMS); protein-based LC/MS with intact proteins (proMS); and nuclear magnetic resonance spectroscopy (NMR). To provide a stringent comparison, we used specific kinases and phosphatases to prepare four samples of Erk in distinct states of phosphorylation and sought to determine the proportion of each of the four phospho-forms in each of the four samples.
We found excellent agreement, to within 10%, between the various biophysical methods, pepMS, proMS and NMR, despite the experiments being carried out in three different laboratories on two different continents. NMR also revealed the presence of two additional phosphorylations on one of the samples, which we identified by MS as serine phosphorylations. We determined most of the corresponding 16 member phospho-form distribution using a combination of pepMS and proMS. To our surprise, however, we found significant semi-quantitative discrepancies between the biophysical and the immunological methods, despite using the LICOR method of ratiometric fluorescent imaging for western blotting. For instance, a phospho-specific antibody may indicate that sample one has a higher proportion of a certain phospho-form than sample two, but pepMS measurements may sometimes indicate the reverse (compare Figures 1D and 2C). We found similar discrepancies with an alternative set of samples, prepared differently (compare Figure 3A and B), and after spiking western blots with whole-cell lysate (Figure 3C) and after using chemiluminescence and CCD imaging in place of fluorescent detection.
Antibodies are usually characterised for the purposes of quantitative measurement by titration against the same sample, but molecular recognition between antibody and antigen is an emergent property of the biological context. In the comparisons made here, the same phospho-form is being examined in different samples and hence in the context of different phospho-form distributions. The antibody sees not only the phospho-epitope that is its nominal target but also differing amounts of other phospho-epitopes against which it may have a range of cross-reactivities. Such a context-dependent interaction may be one reason for the surprising discrepancies that were found. If so, it exemplifies one of our central themes: it is not any single phospho-form that determines the downstream response, in this case of an antibody; it is the entire phospho-form distribution. While antibodies remain unrivalled for protein detection sensitivity amidst complex cellular backgrounds, our results suggest that care is required in using them for quantitative comparisons of post-translational modifications.
If sites can be localised to a single peptide, pepMS with both LC and MS offers good opportunities for separating distinct phospho-forms, including isobaric ones having the same molecular weight. However, such measurements are not quantitative because distinct phospho-forms may ionise and ‘fly' with different efficiencies; isotopically-labelled phospho-peptide internal standards are required for accurate measurements. Moreover, sites on distinct peptides can no longer be correlated with each other. Measurements with intact protein, as in proMS, avoid both problems but are also less sensitive to LC separation, allowing only the distribution of isobaric forms to be determined. The use of multiple samples, prepared with specific phosphatases, can also be informative. The combination of pepMS and proMS offers a hybrid strategy that represents a good balance between coverage and resolution and holds out promise as a general approach for proteins with small numbers of sites. NMR has certain inherent limitations, being unable to detect correlations between phosphorylations that are not close together and being better able to detect phosphorylation on serine and threonine than on tyrosine. However, it has the advantage, as does proMS, of not being biased by prior expectations as to where modifications are expected, illustrated by its uncovering of the two additional phosphorylations on Erk. While NMR's specialised requirements make it less feasible as a general methodology, it holds out the promise of real-time measurements both in vitro and in intact cells.
The problem of quantifying phospho-form distribution remains very challenging as the number of phosphorylated sites increases but quantitative information is now becoming available for proteins such as Erk that are commonly encountered in cellular physiology.
The functional impact of multisite protein phosphorylation can depend on both the numbers and the positions of phosphorylated sites—the global pattern of phosphorylation or ‘phospho-form'—giving biological systems profound capabilities for dynamic information processing. A central problem in quantitative systems biology, therefore, is to measure the ‘phospho-form distribution': the relative amount of each of the 2n phospho-forms of a protein with n-phosphorylation sites. We compared four potential methods—western blots with phospho-specific antibodies, peptide-based liquid chromatography (LC) and mass spectrometry (MS; pepMS), protein-based LC/MS (proMS) and nuclear magnetic resonance spectroscopy (NMR)—on differentially phosphorylated samples of the well-studied mitogen-activated protein kinase Erk2, with two phosphorylation sites. The MS methods were quantitatively consistent with each other and with NMR to within 10%, but western blots, while highly sensitive, showed significant discrepancies with MS. NMR also uncovered two additional phosphorylations, for which a combination of pepMS and proMS yielded an estimate of the 16-member phospho-form distribution. This combined MS strategy provides an optimal mixture of accuracy and coverage for quantifying distributions, but positional isomers remain a challenging problem.
doi:10.1038/msb.2011.15
PMCID: PMC3097084  PMID: 21487401
mass spectrometry, multisite phosphorylation; NMR; phospho-form distribution; phospho-specific antibodies
15.  Prospective Memory, Personality, and Individual Differences 
A number of studies investigating the relationship between personality and prospective memory (ProM) have appeared during the last decade. However, a review of these studies reveals little consistency in their findings and conclusions. To clarify the relationship between ProM and personality, we conducted two studies: a meta-analysis of prior research investigating the relationships between ProM and personality, and a study with 378 participants examining the relationships between ProM, personality, verbal intelligence, and retrospective memory. Our review of prior research revealed great variability in the measures used to assess ProM, and in the methodological quality of prior research; these two factors may partially explain inconsistent findings in the literature. Overall, the meta-analysis revealed very weak correlations (rs ranging from 0.09 to 0.10) between ProM and three of the Big Five factors: Openness, Conscientiousness, and Agreeableness. Our experimental study showed that ProM performance was related to individual differences such as verbal intelligence as well as to personality factors and that the relationship between ProM and personality factors depends on the ProM subdomain. In combination, the two studies suggest that ProM performance is relatively weakly related to personality factors and more strongly related to individual differences in cognitive factors.
doi:10.3389/fpsyg.2013.00130
PMCID: PMC3605513  PMID: 23525147
prospective memory; big five; personality; individual differences; meta-analysis; verbal intelligence; retrospective memory
16.  Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(8):e1001502.
Grace Chan and coauthors conducted a systematic review and meta-analysis of studies evaluating the risk of neonatal infection or colonization during the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Please see later in the article for the Editors' Summary
Background
Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Methods and Findings
We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9–11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1–28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0–5.4) times higher odds of infection than newborns of mothers without risk factors.
Conclusions
Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Millennium Development Goal 4 (MDG4)—one of eight goals agreed by world leaders in 2000 to eradicate extreme poverty globally—aims to reduce under-five mortality (deaths) to one-third of its 1990 level (12 million deaths). Progress towards reducing child mortality has accelerated recently, but MDG4 is unlikely to be met, partly because of slow progress towards reducing neonatal mortality—deaths during the first 28 days of life. Neonatal deaths now account for a greater proportion of global child deaths than in 1990. Nearly half of the children who die before their fifth birthday die during the neonatal period, with babies born in low-middle-income countries in sub-Saharan Africa and southern Asia being at the highest risk of neonatal death. Bacterial infections such as infections of the bloodstream (bacteremia/sepsis), lungs (pneumonia), and the brain's protective covering (meningitis) are responsible for a quarter of neonatal deaths. Newborns can acquire infections during birth by picking up bacteria (in particular Group B streptococcus or GBS) that are present in their mother's reproductive tract and that may or may not cause disease in the mother. Bacteria colonizing the maternal perineum (the area between the anus and the vagina) can move up the vaginal canal into the amniotic sac (the fluid-filled bag in which the baby develops). Maternal bacteremia is another source of bacterial transmission from mother to fetus. Other risk factors for neonatal infection include pre-labor rupture of the membranes (PROM) of the amniotic sac, preterm PROM, and prolonged rupture of membranes.
Why Was This Study Done?
In high-income settings, prophylactic (preventative) antibiotic treatment during labor (based on microbiological screening or risk factors such as PROM) and early diagnosis and treatment of sepsis in newborn babies has greatly reduced deaths from early-onset neonatal bacterial infection. Yet, relatively little is known about the risk factors and transmission pathways for this condition globally. In this global systematic review and meta-analysis, the researchers estimate the risk of neonatal bacterial infections (excluding sexually transmitted diseases) among newborns of mothers with bacterial infection or colonization around the time of birth. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies (only seven of which were undertaken in settings with high neonatal mortality) that included data on laboratory-confirmed maternal infection, maternal infection indicated by clinical signs and symptoms, maternal colonization (positive bacterial cultures from the reproductive tract without any signs or symptoms of infection), or risk factors for infection such as PROM and data on neonatal infection (laboratory-confirmed or clinically indicated) or colonization. Because different studies used different definitions for infection and colonization, the researchers pooled the data from subsets of the studies using random effects meta-analysis, which allows for heterogeneity (inconsistencies) between studies. Newborns of mothers with laboratory-confirmed infection had a 6.6-fold higher risk of laboratory-confirmed infection than newborns born to mothers without laboratory-confirmed infection. Newborns of mothers with bacterial colonization had a 9.4-fold higher risk of laboratory-confirmed infection than newborns of non-colonized mothers. Finally, compared to newborns of mothers without risk factors for infection, newborns of mothers with PROM or other risk factors had a 2.3-fold higher risk of infection.
What Do These Findings Mean?
These findings indicate that an increased risk of early-onset neonatal infection is associated with maternal infection and maternal colonization and provide some quantification of the excess risk. Because all the studies were facility-based and mostly from urban settings in high-income countries, these findings provide no information about the risk of neonatal infection among home births, rural births or births at community facilities in low-income countries, which limits their generalizability. Other aspects of the studies included in this systematic review and meta-analysis are also likely to limit the accuracy of the findings. Nevertheless, these findings suggest that better diagnosis and treatment of maternal infections and colonization in low- to middle-income countries where neonatal mortality is high might substantially reduce the incidence of neonatal infections and that the development of a simple algorithm that combines clinical signs and risk factors to diagnose maternal infections might be useful in regions where laboratory facilities are unavailable. Moreover, they highlight the need for more studies of maternal and neonatal infection and colonization in resource-poor settings with high neonatal mortality.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001502.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about neonatal survival and health; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report and to a video about how new health centers are helping India battle high neonatal death rates
The World Health Organization has information about Millennium Development Goal 4 and about newborn health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information on neonatal infections for parents (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for profit organization; the site also includes a survivor story
doi:10.1371/journal.pmed.1001502
PMCID: PMC3747995  PMID: 23976885
17.  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.
doi:10.1017/S1355617708090012
PMCID: PMC2776623  PMID: 19128527
Human immunodeficiency virus; AIDS dementia complex; Neuropsychological tests; Cognitive science; Patient compliance; Time perception
18.  Prospective Memory in HIV-associated Neurocognitive Disorders (HAND): The Neuropsychological Dynamics of Time Monitoring 
Strategic monitoring during a delay interval is theorized to be an essential feature of time-based prospective memory (TB PM), the cognitive architecture of which is thought to rely heavily on frontostriatal systems and executive functions. This hypothesis was examined in 55 individuals with HIV-associated neurocognitive disorders (HAND) and 108 seronegative comparison participants who were administered the Memory for Intentions Screening Test (MIST), during which time monitoring (clock checking) behavior was measured. Results revealed a significant interaction between HAND group and the frequency of clock checking, in which individuals with HAND monitored checked the clock significantly less often than the comparison group across the TB PM retention intervals of the MIST. Subsequent analyses in the HAND sample revealed that the frequency of clocking checking was positively related to overall TB performance, as well as to standard clinical measures of retrospective memory and verbal fluency. These findings add support to a growing body of research elucidating TB PM’s reliance on strategic monitoring processes dependent upon intact frontostriatal systems. HIV-associated TB strategic time monitoring deficits may manifest in poorer functioning outcomes, including medication non-adherence and dependence in activities of daily living. Future research is needed to further delineate the cognitive mechanisms underlying strategic time monitoring in order to advise rehabilitation strategies for reducing HAND related TB PM deficits.
doi:10.1080/13803395.2013.776010
PMCID: PMC3631446  PMID: 23465043
HIV/AIDS; Prospective memory; Executive functions; Time perception; AIDS dementia complex
19.  Promoter Targeting shRNA Suppresses HIV-1 Infection In vivo Through Transcriptional Gene Silencing 
Despite prolonged and intensive application, combined antiretroviral therapy cannot eradicate human immunodeficiency virus (HIV)-1 because it is harbored as a latent infection, surviving for long periods of time. Alternative approaches are required to overcome the limitations of current therapy. We have been developing a short interfering RNA (siRNA) gene silencing approach. Certain siRNAs targeting promoter regions of genes induce transcriptional gene silencing. We previously reported substantial transcriptional gene silencing of HIV-1 replication by an siRNA targeting the HIV-1 promoter in vitro. In this study, we show that this siRNA, expressed as a short hairpin RNA (shRNA) (shPromA-JRFL) delivered by lentiviral transduction of human peripheral blood mononuclear cells (PBMCs), which are then used to reconstitute NOJ mice, is able to inhibit HIV-1 replication in vivo, whereas a three-base mismatched variant (shPromA-M2) does not. In shPromA-JRFL–treated mice, HIV-1 RNA in serum is significantly reduced, and the ratio of CD4+/CD8+ T cells is significantly elevated. Expression levels of the antisense RNA strand inversely correlates with HIV-1 RNA in serum. The silenced HIV-1 can be reactivated by T-cell activation in ex vivo cultures. HIV-1 suppression is not due to offtarget effects of shPromA-JRFL. These data provide “proof-of principle” that an shRNA targeting the HIV-1 promoter is able to suppress HIV-1 replication in vivo.
doi:10.1038/mtna.2013.64
PMCID: PMC3894581  PMID: 24301868
20.  Transcriptional gene silencing of HIV-1 through promoter targeted RNA is highly specific 
RNA Biology  2011;8(6):1035-1046.
We have previously reported induction of transcriptional gene silencing (TGS) of HIV-1 by short hairpin RNA (shRNA) expressed in MOLT-4 cells. The shRNA (termed shPromA) targets the highly conserved tandem NFκB binding sequences of the HIV-1 promoter. Recent articles have reported that TGS mediated by promoter-targeted siRNAs was exclusively the result of sequence non-specific off-target effects. Specifically, several mismatched siRNAs to the target promoter sequences were reported to also induce significant TGS, suggesting TGS was a consequence of off-target effects. Here, following extensive investigation, we report that shPromA induces sequence specific transcriptional silencing in HIV-1 infection in MOLT-4 cells, while four shRNA variants, mismatched by 2–3 nucleotides, fail to suppress viral replication. We confirm similar levels of shRNA expression from the U6 promoter and the presence of processed/cleaved siRNAs for each construct in transduced MOLT-4 cells. HIV-1 sequence specific shPromA does not suppress HIV-2, which has an alternate NFκB binding sequence. As a result of the unique sequence targeted, shPromA does not induce downregulation of other NFκB driven genes, either at the mRNA or protein level. Furthermore, we confirmed shPromA does not have sequence non-specific off-target effects through unaltered expression of CD4, CXCR4 and CCR5, which are used for viral entry. Additionally, shPromA does not alter PKR, IFN levels, and three downstream mediators of IFNα response genes. Our data clearly shows that shPromA achieved highly specific TGS of HIV-1, demonstrating that effective TGS can be induced with minimal off-target effects.
doi:10.4161/rna.8.6.16264
PMCID: PMC3256422  PMID: 21955498
siRNA; transcriptional-gene-silencing; HIV-1; heterochromatin; NFκB; off-target effects
21.  Combined Effects of Aging and HIV Infection on Semantic Verbal Fluency: A View of the Cortical Hypothesis Through the Lens of Clustering and Switching 
The profile of HIV-associated neurocognitive disorders (HAND) has classically been characterized as “subcortical”, but questions have arisen as to whether aging with HIV in the antiretroviral therapy era has subtlety shifted the expression of HAND into a more “cortical” disorder (e.g., decay of semantic memory stores). We evaluated this hypothesis by examining semantic fluency and its component processes (i.e., clustering and switching) in 257 individuals across four groups stratified by age (<40 and ≥ 50 years) and HIV serostatus. Jonckheere-Terpstra tests revealed significant monotonic trends for the combined effects of HIV and aging on overall semantic (and letter) fluency and switching, but not cluster size, with greatest deficits evident in the older adults with HIV infection. Within the older HIV-infected cohort, poorer switching was uniquely associated with self-reported declines in instrumental activities of daily living and deficits in learning and executive functions, but not semantic memory. Results suggest that HIV infection and aging may confer adverse additive effects on the executive components of semantic fluency (i.e., switching), rather than a degradation of semantic memory stores (i.e., cluster size), which is a profile that is most consistent with combined frontostriatal neuropathological burden of these two conditions.
doi:10.1080/13803395.2011.651103
PMCID: PMC3329578  PMID: 22292479
Immunologic disorders; geropsychology; verbal fluency; executive functions; cognitive neuropsychology
22.  Prospective memory and glycemic control in children with type 1 diabetes mellitus: a cross-sectional study 
Background
Prospective memory is that memory which is required to carry out intended actions and is therefore essential in carrying out the daily activities required in the self-management of type 1 diabetes mellitus (T1DM). This study aimed to identify the relationships between prospective memory and diabetic control in children with T1DM.
Method
94 children aged 6–18 years with T1DM completed an innovative prospective memory screen, PROMS, and a series of cognitive tests. Parents answered questionnaires about their children's diabetic histories and cognitive skills.
Results
No association between total PROMS score and glycemic control was found. Lower HbA1C was associated with higher (better) scores on the 20 minute event-based task on the PROMS. Parental concerns about working memory and metacognition in their children were mirrored by higher HbA1C.
Conclusions
This study suggests that there may be an association between glycemic control and prospective memory for event based tasks. Additional studies need to be done to determine reproducibility, causality, and if prospective memory based interventions can improve diabetic control.
doi:10.1186/1687-9856-2012-29
PMCID: PMC3541107  PMID: 23198726
Hemoglobin A1C; Pediatrics; Adolescents; Psychological testing; Diabetes mellitus; Memory
23.  Longer Ongoing Task Delay Intervals Exacerbate Prospective Memory Deficits in HIV-associated Neurocognitive Disorders (HAND) 
The delay interval between encoding a future intention and detection of the retrieval cue is an essential feature of prospective memory (PM). McDaniel and Einstein’s (2000) multi-process theory posits that greater demands are placed on strategic monitoring processes as the delay interval lengthens. This hypothesis was examined in HIV-associated neurocognitive disorders (HAND), which are associated with strategic dyscontrol of PM likely secondary to prefrontostriatal circuit pathology. Seventy-eight seronegative adults and 49 individuals with HAND comprised the study groups, which were comparable with regard to demographic, psychiatric, and substance use factors. As part of a comprehensive neuropsychological evaluation, participants were administered a well-validated PM measure that included short (2-minute) and long- (15-min) task delay interval scales that utilized a standardized word search as the ongoing task. Results revealed a significant interaction of group and delay interval, with significant effects of HAND on PM at long, but not short delay. The long delay PM effect in HAND was driven primarily by deficits in time-based PM and was most strongly associated with markers of executive dysfunction. In concordance with the multi-process theory, individuals with HAND were disproportionately vulnerable to PM deficits at longer ongoing task delay intervals, which appear to be driven by strategic dyscontrol of PM that is consistent with the preferential disruption of prefrontal systems in neuroAIDS. Difficulty with successfully completing PM tasks following a longer delay could manifest in real-world problems, such as medication nonadherence and unemployment, and characterizing this specific deficit may inform remediation strategies.
doi:10.1080/13803395.2012.654764
PMCID: PMC3311720  PMID: 22299658
Prospective memory; HIV/AIDS; episodic memory; executive functions; time perception; AIDS Dementia Complex
24.  HIV-1 Transmission during Early Infection in Men Who Have Sex with Men: A Phylodynamic Analysis 
PLoS Medicine  2013;10(12):e1001568.
Erik Volz and colleagues use HIV genetic information from a cohort of men who have sex with men in Detroit, USA to dissect the timing of onward transmission during HIV infection.
Please see later in the article for the Editors' Summary
Background
Conventional epidemiological surveillance of infectious diseases is focused on characterization of incident infections and estimation of the number of prevalent infections. Advances in methods for the analysis of the population-level genetic variation of viruses can potentially provide information about donors, not just recipients, of infection. Genetic sequences from many viruses are increasingly abundant, especially HIV, which is routinely sequenced for surveillance of drug resistance mutations. We conducted a phylodynamic analysis of HIV genetic sequence data and surveillance data from a US population of men who have sex with men (MSM) and estimated incidence and transmission rates by stage of infection.
Methods and Findings
We analyzed 662 HIV-1 subtype B sequences collected between October 14, 2004, and February 24, 2012, from MSM in the Detroit metropolitan area, Michigan. These sequences were cross-referenced with a database of 30,200 patients diagnosed with HIV infection in the state of Michigan, which includes clinical information that is informative about the recency of infection at the time of diagnosis. These data were analyzed using recently developed population genetic methods that have enabled the estimation of transmission rates from the population-level genetic diversity of the virus. We found that genetic data are highly informative about HIV donors in ways that standard surveillance data are not. Genetic data are especially informative about the stage of infection of donors at the point of transmission. We estimate that 44.7% (95% CI, 42.2%–46.4%) of transmissions occur during the first year of infection.
Conclusions
In this study, almost half of transmissions occurred within the first year of HIV infection in MSM. Our conclusions may be sensitive to un-modeled intra-host evolutionary dynamics, un-modeled sexual risk behavior, and uncertainty in the stage of infected hosts at the time of sampling. The intensity of transmission during early infection may have significance for public health interventions based on early treatment of newly diagnosed individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first recorded case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. About 34 million people are currently HIV-positive, and about 2.5 million people become newly infected with HIV every year. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having only one or a few partners, and by always using condoms. Most people do not become ill immediately after infection with HIV, although some develop a short flu-like illness. The next stage of HIV infection, which may last more than ten years, also has no major symptoms, but during this stage, HIV slowly destroys immune system cells. Eventually, the immune system can no longer fight off infections by other disease-causing organisms, and HIV-positive people then develop one or more life-threatening AIDS-defining conditions, including unusual infections and specific types of cancer. HIV infection can be controlled, but not cured, by taking a daily cocktail of antiretroviral drugs.
Why Was This Study Done?
The design of effective programs to prevent the spread of HIV/AIDS depends on knowing how HIV transmissibility varies over the course of HIV infection. Consider, for example, a prevention strategy that focuses on increasing treatment rates: antiretroviral drugs, in addition to reducing illness and death among HIV-positive people, reduce HIV transmission from HIV-positive individuals. “Treatment as prevention” can only block transmissions that occur after diagnosis and entry into care. However, the transmissibility of HIV per sexual contact depends on a person's viral load, which peaks during early HIV infection, when people are often unaware of their HIV status and may still be following the high-risk patterns of sexual behavior that caused their own infection. Epidemiological surveillance data (information on HIV infections within populations) can be used to estimate how many new HIV infections occur within a population annually (HIV incidence) and the proportion of the population that is HIV-positive (HIV prevalence), but cannot be used to estimate the timing of transmission events. In this study, the researchers use “phylodynamic analysis” to estimate HIV incidence and prevalence and the timing of HIV transmission during infection. HIV, like many other viruses, rapidly accumulates genetic changes. The timing of transmission influences the pattern of these changes. Viral phylodynamic analysis—the quantitative study of how epidemiological, immunological, and evolutionary processes shape viral phylogenies (evolutionary trees)—can therefore provide estimates of transmission dynamics.
What Did the Researchers Do and Find?
The researchers obtained HIV sequence data (collected for routine surveillance of antiretroviral resistance mutations) and epidemiological surveillance data (including information on the stage of infection at diagnosis) for 662 HIV-positive men who have sex with men living in the Detroit metropolitan area of Michigan. They constructed a phylogenetic tree from the sequences using a “relaxed clock” approach and then fitted an epidemiological model (a mathematical model that represents the progress of individual patients through various stages of HIV infection) to the sequence data. Their approach, which integrates surveillance data and genetic data, yielded estimates of HIV incidence and prevalence among the study population similar to those obtained from surveillance data alone. However, it also provided information about HIV transmission that could not be obtained from surveillance data alone. In particular, it allowed the researchers to estimate that, in the current HIV epidemic among men who have sex with men in Detroit, 44.7% of HIV transmissions occur during the first year of infection.
What Do These Findings Mean?
The robustness of these findings depends on the validity of the assumptions included in the researchers' population genetic model and on the accuracy of the data fed into the model, and may not be generalizable to other cities or to other risk groups. Nevertheless, the findings of this analysis, which can be repeated in any setting where HIV sequence data for individual patients can be linked to patient-specific clinical and behavioral information, have important implications for HIV control strategies based on the early treatment of newly diagnosed individuals. Because relatively few infected individuals are diagnosed during early HIV infection, when the HIV transmission rate is high, it is unlikely, suggest the researchers, that the “treatment as prevention” strategy will effectively control the spread of HIV unless there are very high rates of HIV testing and treatment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001568.
This study is further discussed in a PLOS Medicine Perspective by Timothy Hallett
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV treatment as prevention (in English and Spanish)
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
The US National Institute of Health–funded HIV Sequence Database contains HIV sequences and tools to analyze these sequences
Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV
doi:10.1371/journal.pmed.1001568
PMCID: PMC3858227  PMID: 24339751
25.  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.
doi:10.1080/13854040701595999
PMCID: PMC3057368  PMID: 18756389
reliability; test construction; neuropsychological assessment; episodic memory

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