Financial and recovery worry one year after traumatic injury: A prognostic, registry-based cohort study.

BACKGROUND: Levels of stress post-injury, especially after compensable injury, are known to be associated with worse long-term recovery. It is therefore important to identify how, and in whom, worry and stress manifest post-injury. This study aimed to identify demographic, injury, and compensation factors associated with worry about financial and recovery outcomes 12 months after traumatic injury. METHODS: Participants (n = 433) were recruited from the Victorian Orthopaedic Trauma Outcomes Registry and Victorian State Trauma Registry after admission to a major trauma hospital in Melbourne, Australia. Participants completed questionnaires about pain, compensation experience and psychological wellbeing as part of a registry-based observational study. RESULTS: Linear regressions showed that demographic and injury factors accounted for 11% and 13% of variance in financial and recovery worry, respectively. Specifically, lower education, discharge to inpatient rehabilitation, attributing fault to another and having a compensation claim predicted financial worry. Worry about recovery was only predicted by longer hospital stay and attributing fault to another. In all participants, financial and recovery worry were associated with worse pain (severity, interference, catastrophizing, kinesiophobia, self-efficacy), physical (disability, functioning) and psychological (anxiety, depression, PTSD, perceived injustice) outcomes 12 months post-injury. In participants who had transport (n = 135) or work (n = 22) injury compensation claims, both financial and recovery worry were associated with sustaining permanent impairments, and reporting negative compensation system experience 12 months post-injury. Financial worry 12 months post-injury was associated with not returning to work by 3-6 months post-injury, whereas recovery worry was associated with attributing fault to another, and higher healthcare use at 6-12 months post-injury. CONCLUSIONS: These findings highlight the important contribution of factors other than injury severity, to worry about finances and recovery post-injury. Having a compensation claim, failure to return to work and experiencing pain and psychological symptoms also contribute to elevated worry. As these factors explained less than half of the variance in worry, however, other factors not measured in this study must play a role. As worry may increase the risk of developing secondary mental health conditions, timely access to financial, rehabilitation and psychological supports should be provided to people who are not coping after injury.

Relationship between self-reported cognitive difficulties, objective neuropsychological test performance and psychological distress in chronic pain.

BACKGROUND: Persons with chronic pain often report problems with cognitive abilities, such as memory or attention. There is limited understanding of whether objective performance is consistent with subjective reports, and how psychological factors contribute. We aimed to investigate these relationships in a group of patients expressing cognitive concerns, and evaluate the utility of self-report tools for pain management settings. METHOD: Participants with chronic pain (n = 41) completed standardized neuropsychological tests, and self-report measures of cognitive functioning, pain, mood and sleep, as part of a broader study investigating cognitive performance in pain. RESULTS: Average neuropsychological test performance was subtly below normative means (within one standard deviation). Twenty-five percent of the sample scored substantially below age-adjusted norms on one or more objective tests. There were moderate-to-large associations between objective performance (e.g. Trail-Making B) and subjective cognitive complaints (e.g. Everyday Memory Questionnaire - Revised), controlling for age and education level. This was moderated by anxiety, such that subjective-objective relationships were particularly strong in those with higher anxiety. Poorer test performance was associated with higher pain intensity and catastrophizing. Subjective-objective cognition relationships remained after controlling for catastrophizing. CONCLUSION: Patients' self-reported cognitive concerns concurred with objectively measured performance, independent of age, education and catastrophizing. Moreover, those with severe anxiety were more accurate in predicting their cognitive performance. The findings highlight some interesting cognition-mood relationships, and suggest that easy-to-administer questionnaires, such as the Everyday Memory Questionnaire - Revised and the Behavior Rating Inventory of Executive Function - Adult Version, may be useful to capture cognitive concerns in clinical settings. SIGNIFICANCE: Cognitive concerns in chronic pain reflected objective neurocognitive performance. This was moderated by anxiety, such that self-reported cognition was more consistent with objective performance in those with high anxiety. Our findings suggest that reported cognitive concerns should be heeded, and self-report measures may be used clinically to facilitate dialogue about cognitive functioning.

N-terminal or signal peptide sequence engineering prevents truncation of human monoclonal antibody light chains.

Monoclonal antibodies (mAbs) contain short N-terminal signal peptides on each individual polypeptide that comprises the mature antibody, targeting them for export from the cell in which they are produced. The signal peptide is cleaved from each heavy chain (Hc) and light chain (Lc) polypeptide after translocation to the ER and prior to secretion. This process is generally highly efficient, producing a high proportion of correctly cleaved Hc and Lc polypeptides. However, mis-cleavage of the signal peptide can occur, resulting in truncation or elongation at the N-terminus of the Hc or Lc. This is undesirable for antibody manufacturing as it can impact efficacy and can result in product heterogeneity. Here, we describe a truncated variant of the Lc that was detected during a routine developability assessment of the recombinant human IgG1 MEDI8490 in Chinese hamster ovary cells. We found that the truncation of the Lc was caused due to the use of the murine Hc signal peptide together with a lambda Lc containing an SYE amino acid motif at the N-terminus. This truncation was not caused by mis-processing of the mRNA encoding the Lc and was not dependent on expression platform (transient or stable), the scale of the fed-batch culture or clonal lineage. We further show that using alternative signal peptides or engineering the Lc SYE N-terminal motif prevented the truncation and that this strategy will improve Lc homogeneity of other SYE lambda Lc-containing mAbs. Biotechnol. Bioeng. 2017;114: 1970-1977. © 2017 Wiley Periodicals, Inc.

Location, location, location: Variation in sensitivity to pain across the body.

BACKGROUND: There is evidence that sensitivity to noxious stimuli differs between the sexes and across the body, but few studies have investigated differences in the perception and experience of acute pain stimuli across the body in healthy individuals. METHODS: We recruited 52 healthy participants, aged 18-36 (50% men) and administered 39, 42 and 45 °C stimuli at four body sites bilaterally to examine differences in the experience of pain intensity and unpleasantness between body sites via an 11-point numerical rating scale. RESULTS: Noxious and innocuous thermal heat stimuli were perceived as significantly more intense when delivered to the wrist (M = 3.98, SD = 1.93) and back (M = 4.07, SD = 1.98) compared to the shoulder (M = 3.45, SD = 1.91) and leg (M = 3.46, SD = 1.87). Pain unpleasantness ratings yielded similar findings; stimuli were perceived as more unpleasant when administered to the wrist (M = 2.83, SD = 1.93) and lower back (M = 3.04, SD = 2.11) compared to the shoulder (M = 2.63, SD = 1.85) and leg (M = 2.26, SD = 1.82). CONCLUSIONS: These findings suggest that painful thermal stimuli delivered to the wrist and back are perceived as more intense and unpleasant compared with other body sites in healthy persons. These differences may be due to variations in receptor density, or the relative importance of these sites for daily living and survival. SIGNIFICANCE: Moreover, these insights are helpful for the design of studies investigating pain experience in healthy persons in experimental or clinical settings. WHAT DOES THIS STUDY ADD?: We tested sensitivity to acute suprathreshold thermal stimulations across a range of body sites to investigate for potential variability. We found significant differences in the perceived intensity and unpleasantness of noxious and innocuous thermal stimuli at the wrist and lower back, compared with the shoulder and leg. These results suggest that pain experience is driven by receptor density or the relative functional importance of these sites.

Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of use of cannabis during pregnancy on maternal and fetal outcomes. DATA SOURCES: 7 electronic databases were searched from inception to 1 April 2014. Studies that investigated the effects of use of cannabis during pregnancy on maternal and fetal outcomes were included. STUDY SELECTION: Case-control studies, cross-sectional and cohort studies were included. DATA EXTRACTION AND SYNTHESIS: Data synthesis was undertaken via systematic review and meta-analysis of available evidence. All review stages were conducted independently by 2 reviewers. MAIN OUTCOMES AND MEASURES: Maternal, fetal and neonatal outcomes up to 6 weeks postpartum after exposure to cannabis. Meta-analyses were conducted on variables that had 3 or more studies that measured an outcome in a consistent manner. Outcomes for which meta-analyses were conducted included: anaemia, birth weight, low birth weight, neonatal length, placement in the neonatal intensive care unit, gestational age, head circumference and preterm birth. RESULTS: 24 studies were included in the review. Results of the meta-analysis demonstrated that women who used cannabis during pregnancy had an increase in the odds of anaemia (pooled OR (pOR)=1.36: 95% CI 1.10 to 1.69) compared with women who did not use cannabis during pregnancy. Infants exposed to cannabis in utero had a decrease in birth weight (low birth weight pOR=1.77: 95% CI 1.04 to 3.01; pooled mean difference (pMD) for birth weight=109.42 g: 38.72 to 180.12) compared with infants whose mothers did not use cannabis during pregnancy. Infants exposed to cannabis in utero were also more likely to need placement in the neonatal intensive care unit compared with infants whose mothers did not use cannabis during pregnancy (pOR=2.02: 1.27 to 3.21). CONCLUSIONS AND RELEVANCE: Use of cannabis during pregnancy may increase adverse outcomes for women and their neonates. As use of cannabis gains social acceptance, pregnant women and their medical providers could benefit from health education on potential adverse effects of use of cannabis during pregnancy.

An observational study investigating the impact of simulated patients in teaching communication skills in preclinical dietetic students.

BACKGROUND: Simulated patients (SPs) are often used in dietetics for the teaching and assessment of communication skills. The present study aimed to determine the impact of a SP encounter on communication skills in undergraduate preclinical dietetic students in the context of the resources required for delivering this educational strategy. METHODS: This observational study collected assessment data from four cohorts of third-year dietetic students to examine the effect of participation in SP-embedded Objective Structured Clinical Exams. Students completed two SP interviews, 2 weeks apart, and communication skills were measured on both occasions. A subgroup of students received a video of their SP encounter. Differences between the two SP interview scores were compared to assess the impact of the SP encounter on communication skills. The required staff and resources were described. RESULTS: Data were collected involving 215 students. Out of 30 marks, there was a modest mean (SD) improvement in communication skills from the first to the second SP interview of 2.5 (4.2) (P < 0.01). There was an association between student ability and improvement in communication skills, with failing students demonstrating the greatest improvement between SP encounters. There were no observed benefits for the subset of students who received videos. CONCLUSIONS: Providing repeat SP interview opportunities results in only modest improvement in communication skills for most students. The use of SPs needs to be considered in context of the substantial costs and resources involved and tailored to student ability.

Affective, sensory and empathic sharing of another's pain: The Empathy for Pain Scale.

BACKGROUND: Through two studies, we introduce and validate the Empathy for Pain Scale (EPS), which characterizes the phenomenology of empathy for pain, including the vicarious experience of pain when seeing others in pain. METHODS: In study 1, 406 individuals completed the EPS and Interpersonal Reactivity Index (IRI). In the EPS, four painful scenarios (witnessing surgery, patient recovering from surgery, assault and accidental injury) were rated for 12 emotional, empathic and sensory responses. In study 2, 59 participants completed the same questionnaires and then watched and rated videos of sporting injuries. RESULTS: In study 1, we identified three factors of the EPS with principal component analysis, which were validated with confirmatory factor analysis: affective distress; vicarious pain; and empathic concern. The EPS demonstrated good psychometric properties, re-test reliability (n = 105) and concurrent validity. In study 2, we validated the EPS against empathic reactions to the pain of others as displayed in video clips depicting sporting injuries and showed that the scale has unique utility to characterize empathic reactions to pain above general trait empathy measures. Both studies showed that the affective distress and empathic concern subscales of the EPS correlated with measures of cognitive and affective empathy from the IRI, whereas the vicarious pain subscale was only correlated with the personal distress IRI subscale. CONCLUSIONS: The EPS is a psychometrically sound new scale that characterizes empathy for pain and vicarious pain. The EPS offers valuable insight to the phenomenological profile of the affective, empathic and sensory dimensions of empathy for pain.

Observer-rated pain assessment instruments improve both the detection of pain and the evaluation of pain intensity in people with dementia.

BACKGROUND: Observer-rated pain assessment instruments for people with dementia have proliferated in recent years and are mainly effective in identifying the presence of pain. The objective of this study was to determine whether these tools can also be used to evaluate intensity of pain. METHOD: Quasi-experimental design. Cognitively intact [Mini Mental State Examination (MMSE) ≥ 24, n = 60] and impaired people (MMSE < 20, n = 65) in nursing home facilities took part in the study. Participants were observed at rest and during a movement protocol. Directly afterwards, the observer, blinded to cognitive status, completed three behavioural pain assessment instruments (Abbey Pain Scale, Pain Assessment in Advanced Dementia Scale (PAINAD), Non-communicative Patient's Pain Assessment Instrument (NOPPAIN) ], before interviewing the resident about pain self-report. RESULTS: Significant correlations were found between observer-rated and self-rated measures of pain and were stronger in persons with dementia than in cognitively intact adults. Discriminant function analysis (DFA) revealed: (1) that the use of observer-rated instruments improved recognition of the presence or absence of pain by up to 25.4% (in dementia) and 28.3% (in cognitively intact adults) above chance; and (2) the same instruments improved the classification of residents into the correct self-reported level of pain intensity by up to 42.5% (in dementia) and 34.1% (in cognitively intact adults) above chance. However, DFA also reveals a considerable rate of 'false alarms' for pain in cognitively intact and 'misses' in cognitively impaired people. CONCLUSIONS: The use of the Abbey Pain Scale, PAINAD or NOPPAIN improves both the recognition of pain presence/absence as well as rating pain severity in older people with impaired cognition.

Chronic pain in inflammatory bowel disease: characteristics and associations of a hospital-based cohort.

BACKGROUND: Chronic pain (CP) is a common symptom in patients with inflammatory bowel disease. This study aimed to examine its prevalence, severity, clinical associations, and impact on psychological well-being and to identify patient factors that independently predict the presence of severe/disabling pain. METHODS: One hundred and twenty consecutive patients with inflammatory bowel disease attending a hospital-based clinic provided information through questionnaires on quality of life, mood disturbance, and functional gut symptoms. Those who had CP (pain occurring every day for 3 months within the past 6 months) provided additional information on the pain's intensity and associated disability and management and coping strategies. RESULTS: Forty-six patients (38%) had CP, most commonly in the abdomen (91%), and they had higher disease activity, reduced quality of life, and more depression and anxiety and took more paracetamol and opiates than those without. These indices were worse in the subgroup of 23 with moderate-severe pain/disability. Criteria for irritable bowel syndrome were met in 70% of those with pain irrespective of its severity. Multivariate analysis identified 4 independent associations with moderate-severe pain/disability: active disease (odds ratio, 49 [95% confidence intervals, 1.6-1455]), catastrophizing tendency (35 [3-228]), medication belief score (0.05 [0.005-0.55], and depression score (1.80 [1.02-3.17]). CONCLUSIONS: CP has major effects on quality of life and functional and social outcomes. Active disease and maladaptive coping strategies and negative attitudes and beliefs toward symptoms are independently associated with more severe pain. Management strategies should move the focus away from analgesic dependence toward psychosocial intervention and nonpharmacologic therapy.

On the moderating role of age in the relationship between pain and cognition.

BACKGROUND: A relationship between pain perception and cognitive function is evident. However, the directionality of this association is unclear and may be influenced by age. That is, inverse associations between pain and cognition have been reported in young and middle-aged chronic pain patients, whereas higher clinical pain ratings have been associated with better cognitive performance in older chronic pain patients. Therefore, this study examined the possible moderating role of age in the pain-cognition relationship. METHOD: Twenty-two younger and 24 older chronic pain participants completed neuropsychological tests of psychomotor speed, memory and executive function. They also completed the McGill Pain Questionnaire to evaluate clinical pain. RESULTS: Interaction analyses revealed that age indeed moderates the relationship between clinical pain ratings and cognitive functions. In the younger age group, pain ratings were inversely related to memory and executive function. In the older age group, a positive relationship was found between pain ratings and executive function, whereas the inverse association of clinical pain with memory was no longer present. CONCLUSIONS: This study was the first to confirm the hypothesis that age is an important moderator of the relationship between pain and cognition. An important finding is that in older adults, most inverse effects of pain on cognition are either no longer present or may even be reversed. The positive relationship between pain and executive function may indicate age-related reduced integrity of a shared underlying neural substrate.

Pain and dementia: a diagnostic challenge.

PURPOSE: The aim was to present current knowledge about pain assessment in people with dementia and to discuss special challenges and possible solutions. METHODS: A literature search in MEDLINE® was performed. RESULTS: Due to the changing demographics of an aging population, an increasing number of people with dementia is expected. Many of these people will simultaneously suffer pain. Under-detection and under-treatment of pain in persons suffering from dementia is often described. As dementia progresses, the ability of the sufferer to verbally communicate his/her pain is often compromised, complicating the task of recognizing and treating pain. To improve pain recognition in dementia, many pain assessment tools have been developed. However, psychometric properties have to date been insufficiently examined. IMPLICATIONS: Self-report ratings should be performed as long as justifiable. Behavioural pain assessment tools should be used in advanced dementia despite their current imperfections: in particular, the PAINAD for daily use and the PACSLAC at longer intervals. All available additional information about pain should be considered.

Reliability study in five languages of the translation of the pain behavioural scale Doloplus.

Non-verbal pain assessment scales are useful tools for pain evaluation in persons with communication disorders and moderate-severe dementia. The Doloplus was one of the first scales to be developed and validated as a pain assessment tool in older adults with dementia. This study aims at evaluating the translation of the Doloplus scale in five languages, as regards test-retest and inter-rater reliability. Results show that both tests are good or excellent for the English, Italian, Portuguese and Spanish versions and moderate for the Dutch version. These results bring a unique opportunity to include the translated Doloplus scale in daily assessment of elderly persons with communication disorders, and future studies should focus on enriching the validation of the scale in each language.

Computer assisted age progression.

A computer assisted method for altering the perceived age of a human face is presented. Our technique is based on calculating a trajectory or axis within a multi-dimensional space that captures the changes in large scale facial structure, shading and complexion associated with aging. Fine facial details associated with increasing age, such as wrinkles, are added to the aged face using a variation on a standard image processing technique called high boost filtering. The method is successfully applied to two-dimensional photographic images exhibiting uncontrolled variations in pose and illumination. Unlike our previous work on automated age progression, here the objective is to allow a certain degree of manual control over the process by the adjustment of three key progression-control-parameters. In the future this work may form the basis for a software tool to be used by forensic artists.

Geriatric syndromes as predictors of adverse outcomes of hospitalization.

AIMS: The aim of this study was to determine the association between the common geriatric syndromes and predefined adverse outcomes of hospitalization and to identify the most important independent predictors of adverse outcomes using information gained within 24 h of admission in older general medical patients. METHODS: A prospective longitudinal cohort study of patients aged > or =75 years admitted to the rapid assessment medical unit in a teaching hospital was carried out. The role of geriatric syndromes in predicting outcomes was examined in univariate and multivariate models. The outcome measures were (i) length of hospital stay (LOS) of 28 days or more, (ii) institutionalization or change in residential care status to a more dependent category at discharge or during 3 months post-discharge, (iii) unplanned readmissions during 3 months and (iv) mortality in hospital or 3 months post-discharge. RESULTS: The presence of geriatric syndromes was significantly associated with increased LOS and institutionalization or change in residential care status to a more dependent category. The factors most predictive of these outcomes were impaired pre-admission functional status in activities of daily living, recurrent falls, urinary incontinence and supported living arrangements. The geriatric syndromes appeared less important in predicting unplanned readmission and death. CONCLUSION: The presence of geriatric syndromes in older general medical patients is an important determinant of adverse outcomes of hospitalization, particularly of LOS and admission to residential care. The predictors most useful for screening patients for these outcomes, within 24 h of admission, appear to be the presence of certain pre-existing geriatric syndromes before admission.

Methodologic factors which contribute to variations in experimental pain threshold reported for older people.

Using the same study groups and psychophysical methods, we have tested the hypothesis that variations in pain threshold with advancing age are best explained by variations in stimulus duration. Fifteen young adults and 15 older people without clinical evidence of neurologic disease or psychologic dysfunction had pain thresholds determined with heat and electrical stimuli using the method of limits; for electrical stimulation a double random staircase design was used. The stimulus duration was 1-100 s for heat and 50-5000 ms for electrical stimulation. It was found that older people have an increased threshold for thermal and electrically induced pain if the stimulus duration is kept short. This result explains much of the variability in age associated pain threshold in the literature.

Development of a pain attitudes questionnaire to assess stoicism and cautiousness for possible age differences.

This study aimed to develop a pain attitudes questionnaire (PAQ) and examine its reliability and validity for use in assessing the constructs of stoicism and cautiousness relevant to pain perception. The questionnaire was administered to 373 healthy community-dwelling individuals who were subsequently divided into four age groups to test for differences in stoicism and cautiousness, two attitudes that have previously been claimed to influence pain perception and report among older adults. Factor analysis revealed that two dimensions of stoicism and two dimensions of cautiousness are measured by the scale, with reticence and superiority characterizing the first construct and self-doubt and reluctance characterizing the second. There was support for the scale's reliability and validity. Age-related increase in degree of reticence to pain, self-doubt, and reluctance to label a sensation as painful was found, emphasizing the need for careful consideration of pain attitudes in older patients who may underreport their pain symptoms.

The epidemiology of pain in elderly people.

Acute pain probably occurs at much the same rate across all age groups. On the other hand, self-report of chronic pain seems to increase up to, but not beyond, the seventh decade of life. Chronic pain in older people is more often experienced in major joints, the back, legs and feet, whereas visceral pain and headache are reported less often. There is a divergence between an increasing load of pain-associated disease and a plateau of chronic pain complaint in old age that probably reflects impairment in the nociceptive function of the nervous system. However, the contribution of social, behavioral, cognitive, and affective dimensions of the pain experience to this divergence between disease and pain have not been fully evaluated. Most of the answers to these and other questions require longitudinal studies with pain as the predominant focus of attention rather than addressing the symptom of pain as an ancillary measure relevant to other aspects of aging.

Age-related differences in pain perception and report.

The clinical and laboratory-based evidence for age-related differences in pain perception and report are reviewed. Most clinical studies suggest a relative decrease in the frequency and intensity of pain symptoms associated with myocardial complaints, visceral infections, musculoskeletal conditions, and postoperative and malignant pain problems in adults of advanced age. The findings from experimentally controlled laboratory investigations are more equivocal and vary according to the type and intensity of noxious stimulation. Nonetheless, such studies also provide some additional support for the notion of an age-related decrease in pain perception and report. Evidence has not determined whether the observed changes are caused by the aging process or reflect other age-associated effects, including an increased presence of comorbid disease, biocultural cohort effects, or altered psychosocial influences.

An examination of pain perception and cerebral event-related potentials following carbon dioxide laser stimulation in patients with Alzheimer's disease and age-matched control volunteers.

BACKGROUND: Pain perception is known to depend on integrated cognitive processing. Alzheimer's disease affects 5% to 10% of older adults, but the impact of this disease on pain sensitivity and report has yet to be fully investigated. AIM OF INVESTIGATION: The present study examined pain threshold, the reliability of pain report and the central nervous system processing of noxious input, as indexed by cerebral event-related potentials (CERP). METHODS: Carbon dioxide laser detection and heat pain thresholds were determined on the hand dorsum of 15 healthy older adults (Mini-Mental State Examination [MMSE] score 29.9 +/- 0.3) and 15 persons with cognitive impairment (MMSE score 12.7 +/- 6.1). Using an array of 15 silver/silver chloride scalp electrodes, the CERP and subjective rating of stimulus intensity were recorded after fixed intensity, 25 W laser stimuli. RESULTS: Compared with age-matched controls, the detection threshold for just noticeable sensation was significantly increased in elderly adults suffering from Alzheimer's disease. There was no difference in pain threshold intensity between persons with cognitive impairment and controls, although the former group was less reliable in reporting detection and pain threshold sensations. The subjective rating of a 25 W stimulus was virtually identical in both groups, and the amplitude of the major CERP component (P400) was similar; however, cognitively impaired adults exhibited a significant increase in the latency of the P400 response. CONCLUSIONS: The present findings indicate that pain perception in response to an acute heat pain stimulus is not diminished in older persons with cognitive impairment. Patients with Alzheimer's disease may be slightly less reliable in threshold pain report, although the subjective rating of evoked pain and the level of poststimulus cortical activation following noxious stimulation were found to be similar to those of controls. A longer latency of the CERP may suggest slower cortical processing of nociceptive input by persons with Alzheimer's disease.

Adjuvant activities of immune response modifier R-848: comparison with CpG ODN.

R-848 and imiquimod belong to a class of immune response modifiers that are potent inducers of cytokines, including IFN-alpha, TNF-alpha, IL-12, and IFN-gamma. Many of these cytokines can affect the acquired immune response. This study examines the effects of R-848 on aspects of acquired immunity, including immunoglobulin secretion, in vivo cytokine production, and Ag-specific T cell cytokine production. Results are compared with those of Th1 CpG ODN. R-848 and CpG ODN are effective at skewing immunity in the presence of Alum toward a Th1 Ab response (IgG2a) and away from a Th2 Ab response (IgE). R-848 and CpG ODN are also capable of initiating an immune response in the absence of additional adjuvant by specifically enhancing IgG2a levels. Both R-848 and imiquimod showed activity when given subcutaneously or orally, indicating that the compound mechanism was not through generation of a depot effect. Although CpG ODN behaves similarly to R-848, CpG ODN has a distinct cytokine profile, is more effective than R-848 when given with Alum in the priming dose, and is active only when given by the same route as the Ag. The mechanism of R-848's adjuvant activity is linked to cytokine production, where increases in IgG2a levels are associated with IFN-alpha, TNF-alpha, IL-12, and IFN-gamma induction, and decreases in IgE levels are associated with IFN-alpha and TNF-alpha. Imiquimod also enhances IgG2a production when given with Ag. The above results suggest that the imidazoquinolines R-848 and imiquimod may be attractive compounds for use as vaccine adjuvants and in inhibiting pathological responses mediated by Th2 cytokines.