The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya.

BACKGROUND: Further reductions in malaria incidence as more countries approach malaria elimination require the identification and treatment of asymptomatic individuals who carry mosquito-infective Plasmodium gametocytes that are responsible for furthering malaria transmission. Assessing the relationship between total parasitaemia and gametocytaemia in field surveys can provide insight as to whether detection of low-density, asymptomatic Plasmodium falciparum infections with sensitive molecular methods can adequately detect the majority of infected individuals who are potentially capable of onward transmission. METHODS: In a cross-sectional survey of 1354 healthy children and adults in three communities in western Kenya across a gradient of malaria transmission (Ajigo, Webuye, and Kapsisywa-Kipsamoite), asymptomatic P. falciparum infections were screened by rapid diagnostic tests, blood smear, and quantitative PCR of dried blood spots targeting the varATS gene in genomic DNA. A multiplex quantitative reverse-transcriptase PCR assay targeting female and male gametocyte genes (pfs25, pfs230p), a gene with a transcriptional pattern restricted to asexual blood stages (piesp2), and human GAPDH was also developed to determine total parasite and gametocyte densities among parasitaemic individuals. RESULTS: The prevalence of varATS-detectable asymptomatic infections was greatest in Ajigo (42%), followed by Webuye (10%). Only two infections were detected in Kapsisywa. No infections were detected in Kipsamoite. Across all communities, children aged 11-15 years account for the greatest proportion total and sub-microscopic asymptomatic infections. In younger age groups, the majority of infections were detectable by microscopy, while 68% of asymptomatically infected adults (> 21 years old) had sub-microscopic parasitaemia. Piesp2-derived parasite densities correlated poorly with microscopy-determined parasite densities in patent infections relative to varATS-based detection. In general, both male and female gametocytaemia increased with increasing varATS-derived total parasitaemia. A substantial proportion (41.7%) of individuals with potential for onward transmission had qPCR-estimated parasite densities below the limit of microscopic detection, but above the detectable limit of varATS qPCR. CONCLUSIONS: This assessment of parasitaemia and gametocytaemia in three communities with different transmission intensities revealed evidence of a substantial sub-patent infectious reservoir among asymptomatic carriers of P. falciparum. Experimental studies are needed to definitively determine whether the low-density infections in communities such as Ajigo and Webuye contribute significantly to malaria transmission.

Synergistic malaria vaccine combinations identified by systematic antigen screening.

A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.

A conditional predictive p-value to compare a multinomial with an overdispersed multinomial in the analysis of T-cell populations.

Immunological experiments that record primary molecular sequences of T-cell receptors produce moderate to high-dimensional categorical data, some of which may be subject to extra-multinomial variation caused by technical constraints of cell-based assays. Motivated by such experiments in melanoma research, we develop a statistical procedure for testing the equality of two discrete populations, where one population delivers multinomial data and the other is subject to a specific form of overdispersion. The procedure computes a conditional-predictive p-value by splitting the data set into two, obtaining a predictive distribution for one piece given the other, and using the observed predictive ordinate to generate a p-value. The procedure has a simple interpretation, requires fewer modeling assumptions than would be required of a fully Bayesian analysis, and has reasonable operating characteristics as evidenced empirically and by asymptotic analysis.

RheumMadness Over Two Years: Engaging Participants in Active Learning and Connecting Early Trainees to the Rheumatology Community.

OBJECTIVE: RheumMadness is an online learning collaborative that seeks to actively engage the rheumatology community. The objective of this manuscript is to analyze the educational experience of RheumMadness over two years. METHODS: Direct measures of participant engagement were obtained using web-based analytics. An electronic survey was created after the tournament to capture self-reported engagement and educational experience using the Community of Inquiry framework. Data were analyzed according to the following objectives: (1) compare demographics, engagement, and educational experience of participants between 2021 and 2022; (2) describe the educational experience of those who created scouting reports; (3) explore the impact of RheumMadness on early learners (medical students and residents). RESULTS: Compared with 2021, the 2022 tournament had more participants who submitted a bracket, more early learners, and more scouting report creators. Self-reported engagement and educational experience was high in both years of the tournament among all participants. Over 85% of scouting report creators reported that making a report was a fun and valuable learning experience. Early learners reported significantly higher levels of knowledge integration, sense of belonging in the rheumatology community, social connection, and overall learning experience compared with more advanced participants. Eighty-five percent of early learners reported that RheumMadness increased their interest in rheumatology. CONCLUSION: RheumMadness expanded from 2021 to 2022, engaging more participants in collaborative learning. Our results demonstrate that RheumMadness is particularly impactful among medical students and residents by helping them explore rheumatology topics and connect with the rheumatology community.

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine.

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.

Checkpoint Inhibitor-Associated Scleroderma and Scleroderma Mimics.

Immune checkpoint inhibitors (ICI) are the standard of care for various malignancies and have been associated with a wide spectrum of complications that are phenotypically akin to primary autoimmune diseases. While the literature on these toxicities is growing, there is a paucity of data regarding ICI-associated scleroderma which can carry significant morbidity and limit the ability to continue effective ICI therapy. Our review aimed to analyze the current literature on ICI-associated systemic scleroderma (ICI-SSc) and key scleroderma mimics. Cases of ICI-SSc had notable differences from primary SSc, such as fewer vascular features and less seropositivity (such as scleroderma-specific antibodies and antinuclear antibodies). We found that patients with a diagnosis of SSc prior to the start of ICI can also experience flares of pre-existing disease after ICI treatment used for their cancer. Regarding scleroderma mimics, several cases of ICI-eosinophilic fasciitis have also been described with variable clinical presentations and courses. We found no cases of scleroderma mimics: ICI-scleromyxedema or ICI-scleroedema. There is a critical need for multi-institutional efforts to collaborate on developing a patient database and conducting robust, prospective research on ICI-scleroderma. This will ultimately facilitate more effective clinical evaluations and management for ICI-scleroderma.

Linking Adiposity to Interstitial Lung Disease: The Role of the Dysfunctional Adipocyte and Inflammation.

Adipose tissue has functions beyond its principal functions in energy storage, including endocrine and immune functions. When faced with a surplus of energy, the functions of adipose tissue expand by mechanisms that can be both adaptive and detrimental. These detrimental adipose tissue functions can alter normal hormonal signaling and promote local and systemic inflammation with wide-ranging consequences. Although the mechanisms by which adipose tissue triggers metabolic dysfunction and local inflammation have been well described, little is known about the relationship between adiposity and the pathogenesis of chronic lung conditions, such as interstitial lung disease (ILD). In this review, we detail the conditions and mechanisms by which adipose tissue becomes dysfunctional and relate this dysfunction to inflammatory changes observed in various forms of ILD. Finally, we review the existing basic and clinical science literature linking adiposity to ILD, highlighting the need for additional research on the mechanisms of adipocyte-mediated inflammation in ILD and its clinical implications.

Acute Kidney Injury Related to Intoxication From Synthetic Cannabis: Don't You Know That You're Toxic?

Acute kidney injury (AKI) occurs infrequently in young patients and often raises concern for irreversible or deadly etiologies. However, AKI related to synthetic marijuana, colloquially known as K2, is an increasingly common phenomenon in the United States and resolves quickly with fluid resuscitation. Here, we present a case of a young male who presented with severe AKI that initially raised concern for the need to start renal replacement therapy. Laboratory testing revealed an elevated osmolar gap and negative urine drug screen, while urinalysis demonstrated acanthocytes, raising concern for toxic alcohol ingestion or vasculitis. Following fluid resuscitation, his renal function improved dramatically, and he was discharged home within days of presentation. K2-related AKI most frequently occurs in young men, mirroring the population that most frequently uses synthetic marijuana. Its exact etiology remains unknown, but direct nephrotoxicity appears to be the most plausible mechanism. No other known case has reported acanthocytes. Although objective data indicates severe illness on presentation, patients often recover rapidly to baseline and often do not suffer long-term renal impairment following conservative management.

Melanoma-induced suppression of tumor antigen-specific T cell expansion is comparable to suppression of global T cell expansion.

We have observed that in vivo interaction between melanoma and resting T cells promotes suppression of antigen-driven proliferative T cell expansion. We hypothesized that this suppression would affect tumor antigen-specific T cell populations more potently than tumor-unrelated T cell populations. A B16F10 cell line was stably transfected to express low levels of the lymphocytic choriomeningitis virus (LCMV) glycoprotein GP33 (B16GP33). Mice bearing B16F10 or B16GP33 tumors were infected with LCMV, and proliferative expansion of LCMV epitope-specific T cell populations was quantified. In vitro and in vivo assays confirmed low levels of antigenic GP33 expression by B16GP33 tumors. Suppressed expansion of GP33-specific T cells was equivalent between mice bearing B16F10 and B16GP33 tumors. These observations suggest that the ability of growing melanoma tumors to impair antigen-driven proliferative expansion of activated T cells is global and not antigen-specific, and provide further insight into the influence of cancer on activated T cell homeostasis.

Probing reward function in posttraumatic stress disorder: expectancy and satisfaction with monetary gains and losses.

BACKGROUND: Posttraumatic stress disorder (PTSD) may be associated with dysfunctional reward processing. The present study assessed for such dysfunction in both the expectancy and outcome phases of reward processing. METHODS: Male Vietnam veterans with (n=15) and without (n=11) combat-related PTSD were administered a wheel of fortune-type gambling task. Self-reported ratings of expectancy and satisfaction were collected respectively before and after each experience of monetary gain or loss. RESULTS: PTSD participants reported both lower expectancy of reward and lower satisfaction with reward when it was received. The latter result was manifest in a failure of PTSD participants to show the greater satisfaction that normally accompanies rewards received under conditions of low expectancy. CONCLUSION: These results suggest reward function impairment in PTSD related to expectancy, satisfaction, and the expectancy-satisfaction relationship.

A phase I study of immunization using particle-mediated epidermal delivery of genes for gp100 and GM-CSF into uninvolved skin of melanoma patients.

PURPOSE: We examined in vivo particle-mediated epidermal delivery (PMED) of cDNAs for gp100 and granulocyte macrophage colony-stimulating factor (GM-CSF) into uninvolved skin of melanoma patients. The aims of this phase I study were to assess the safety and immunologic effects of PMED of these genes in melanoma patients. EXPERIMENTAL DESIGN: Two treatment groups of six patients each were evaluated. Group I received PMED with cDNA for gp100, and group II received PMED with cDNA for GM-CSF followed by PMED for gp100 at the same site. One vaccine site per treatment cycle was biopsied and divided for protein extraction and sectioning to assess transgene expression, gold-bead penetration, and dendritic cell infiltration. Exploratory immunologic monitoring of HLA-A2(+) patients included flow cytometric analyses of peripheral blood lymphocytes and evaluation of delayed-type hypersensitivity to gp100 peptide. RESULTS: Local toxicity in both groups was mild and resolved within 2 weeks. No systemic toxicity could be attributed to the vaccines. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. GM-CSF transgene expression in vaccinated skin sites was detected. GM-CSF and gp100 PMED yielded a greater infiltration of dendritic cells into vaccine sites than did gp100 PMED only. Exploratory immunologic monitoring suggested modest activation of an antimelanoma response. CONCLUSIONS: PMED with cDNAs for gp100 alone or in combination with GM-CSF is well tolerated by patients with melanoma. Moreover, pathologic autoimmunity was not shown. This technique yields biologically active transgene expression in normal human skin. Although modest immune responses were observed, additional investigation is needed to determine how to best utilize PMED to induce antimelanoma immune responses.

Pilot study of safety and feasibility of DNA microseeding for treatment of spontaneous canine melanoma.

Spontaneous canine malignant melanoma provides an excellent pre-clinical model to study DNA vaccines for melanoma immunotherapy. A USDA-approved xenogeneic human tyrosinase (huTYR) plasmid DNA vaccine delivered intramuscularly induces detectable immune responses and has clinical activity in some dogs with melanoma. The objective of this pilot study was to evaluate the feasibility, safety and immunogenicity of huTYR plasmid DNA administered to the skin via microseeding in dogs with spontaneous melanoma. DNA microseeding utilizes a modified tattooing device as an alternate and potentially more potent delivery method for DNA immunization. DNA was delivered to shaved inner thigh skin of six companion dogs with melanoma approximately every 14 days for a planned total of four vaccination time points. An anti-huTYR ELISA was used to test pre- and post-treatment sera. Biopsies of treated skin were obtained for detection of huTYR transgene expression. DNA microseeding was well tolerated with no significant toxicity detected beyond local site irritation, and there were no signs of autoimmunity. huTYR-expressing cells were observed in biopsies of huTYR DNA microseeding sites. Increased humoral anti-huTYR antibodies were seen in two of five evaluable dogs following microseeding compared to baseline. DNA microseeding is well tolerated in companion dogs with melanoma. Further investigation is needed to determine if combining DNA microseeding with other immunotherapy regimens potentiates this delivery platform for cancer immunotherapy.

A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder.

BACKGROUND: Previous functional neuroimaging studies have demonstrated exaggerated amygdala responses and diminished medial prefrontal cortex responses during the symptomatic state in posttraumatic stress disorder (PTSD). OBJECTIVES: To determine whether these abnormalities also occur in response to overtly presented affective stimuli unrelated to trauma; to examine the functional relationship between the amygdala and medial prefrontal cortex and their relationship to PTSD symptom severity in response to these stimuli; and to determine whether responsivity of these regions habituates normally across repeated stimulus presentations in PTSD. DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Volunteer sample of 13 men with PTSD (PTSD group) and 13 trauma-exposed men without PTSD (control group). MAIN OUTCOME MEASURES: We used functional magnetic resonance imaging (fMRI) to study blood oxygenation level-dependent signal during the presentation of emotional facial expressions. RESULTS: The PTSD group exhibited exaggerated amygdala responses and diminished medial prefrontal cortex responses to fearful vs happy facial expressions. In addition, in the PTSD group, blood oxygenation level-dependent signal changes in the amygdala were negatively correlated with signal changes in the medial prefrontal cortex, and symptom severity was negatively related to blood oxygenation level-dependent signal changes in the medial prefrontal cortex. Finally, relative to the control group, the PTSD group tended to exhibit diminished habituation of fearful vs happy responses in the right amygdala across functional runs, although this effect did not exceed our a priori statistical threshold. CONCLUSIONS: These results provide evidence for exaggerated amygdala responsivity, diminished medial prefrontal cortex responsivity, and a reciprocal relationship between these 2 regions during passive viewing of overtly presented affective stimuli unrelated to trauma in PTSD.

Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder.

BACKGROUND: Larger heart rate responses to sudden, loud (startling) tones represent one of the best-replicated psychophysiologic markers for posttraumatic stress disorder (PTSD). This abnormality may be a pretrauma vulnerability factor, ie, it may have been present prior to the event's occurrence and increased the individual's likelihood of developing PTSD on traumatic exposure. Alternately, it may be an acquired PTSD sign, ie, it may have developed after the traumatic exposure, along with the PTSD. Studying identical twins discordant for traumatic exposure offers an opportunity to resolve these competing origins. METHODS: Subjects included pairs of Vietnam combat veterans and their non-combat-exposed, monozygotic twins. Combat veterans were diagnosed as having current PTSD (n = 50) or non-PTSD (ie, never had) (n = 53). All subjects listened to a series of 15 sudden, loud tone presentations while heart rate, skin conductance, and orbicularis oculi electromyogram responses were measured. RESULTS: Consistent with previous reports, averaged heart rate responses to the tones were larger in Vietnam combat veterans with PTSD. These larger responses were not shared by their non-combat-exposed co-twins, whose responses were similar to those of the non-PTSD combat veterans and their non-combat-exposed co-twins. This result remained significant after adjusting for a number of potentially confounding factors. CONCLUSIONS: The results suggest that larger heart rate responses to sudden, loud tones represent an acquired sign of PTSD rather than a familial vulnerability factor.

Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.

CONTEXT: Theoretical neuroanatomic models of posttraumatic stress disorder (PTSD) and the results of previous neuroimaging studies of PTSD highlight the potential importance of the amygdala and medial prefrontal regions in this disorder. However, the functional relationship between these brain regions in PTSD has not been directly examined. OBJECTIVE: To examine the relationship between the amygdala and medial prefrontal regions during symptom provocation in male combat veterans (MCVs) and female nurse veterans (FNVs) with PTSD. DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Volunteer sample of 17 (7 men and 10 women) Vietnam veterans with PTSD (PTSD group) and 19 (9 men and 10 women) Vietnam veterans without PTSD (control group). MAIN OUTCOME MEASURES: We used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the recollection of personal traumatic and neutral events. Psychophysiologic and emotional self-report data also were obtained to confirm the intended effects of script-driven imagery. RESULTS: The PTSD group exhibited rCBF decreases in medial frontal gyrus in the traumatic vs neutral comparison. When this comparison was conducted separately by subgroup, MCVs and FNVs with PTSD exhibited these medial frontal gyrus decreases. Only MCVs exhibited rCBF increases in the left amygdala. However, for both subgroups with PTSD, rCBF changes in medial frontal gyrus were inversely correlated with rCBF changes in the left amygdala and the right amygdala/periamygdaloid cortex. Furthermore, in the traumatic condition, for both subgroups with PTSD, symptom severity was positively related to rCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus. CONCLUSIONS: These results suggest a reciprocal relationship between medial prefrontal cortex and amygdala function in PTSD and opposing associations between activity in these regions and symptom severity consistent with current functional neuroanatomic models of this disorder.

Probing reward function in post-traumatic stress disorder with beautiful facial images.

Reward dysfunction may be implicated in post-traumatic stress disorder (PTSD). This study applied a behavioral probe, known to activate brain reward regions, to subjects with PTSD. Male heterosexual Vietnam veterans with (n = 12) or without (n = 11) current PTSD were administered two tasks: (a) key pressing to change the viewing time of average or beautiful female or male facial images, and (b) rating the attractiveness of these images. There were no significant group differences in the attractiveness ratings. However, PTSD patients expended less effort to extend the viewing time of the beautiful female faces. These findings suggest a reward deficit in PTSD.

Predicting emotional responses to potentially traumatic events from pre-exposure waking cortisol levels: a longitudinal study of police and firefighters.

There is a large literature demonstrating that individuals who have experienced traumatic events have alterations in the hypothalamic-pituitary-adrenal (HPA) axis. However, the existing literature does not address the extent to which these alterations represent pre-existing risk factors for developing psychopathology upon exposure to a significant stressor. In the current study, we examined the relationship between waking salivary cortisol level and physiological, personality, and psychological measures in 60 firefighters and police trainees during training, and then again after exposure to a highly stressful, potentially traumatic event (PTE). Waking cortisol was negatively associated with neuroticism, but positively associated with physiological reactivity to loud tones and fear conditioning when assessed during training. Longitudinally, there were significant negative correlations between pre-PTE waking cortisol and post-PTE negative mood and anxiety symptoms, but a positive correlation (trend) between pre-PTE waking cortisol and post-PTE physiological reactivity during recollection of the PTE. Thus, waking cortisol level may serve to predict divergent types of emotional sequelae following PTEs.

Psychophysiological assessment of PTSD: a potential research domain criteria construct.

Most research on posttraumatic stress disorder (PTSD) relies on clinician-administered interview and self-report measures to establish the presence/absence and severity of the disorder. Accurate diagnosis of PTSD is made challenging by the presence of symptoms shared with other psychopathologies and the subjective nature of patients' descriptions of their symptoms. A physiological assessment capable of reliably "diagnosing" PTSD could provide adjunctive information that might mitigate these diagnostic limitations. In the present study, we examined the construct validity of a potential psychophysiological measure of PTSD, that is, psychophysiological reactivity to script-driven imagery (SDI-PR), as measured against the current diagnostic "gold-standard" for PTSD, the Clinician-Administered PTSD Scale (CAPS). Convergent and predictive validity and stability were examined. Thirty-six individuals completed an SDI-PR procedure, the CAPS, and self-report measures of mental and physical health at their initial visit and approximately 6 months later. SDI-PR and the CAPS demonstrated excellent stability across measurement occasions. SDI-PR showed moderately strong convergent validity with the CAPS. After adjusting for self-reported depression, predictive validity for the CAPS, with regard to health sequelae, was reduced, whereas it remained mostly unchanged for SDI-PR. Findings support SDI-PR as a valid and stable measure of PTSD that captures a pathophysiologic process in individuals with PTSD. Results are discussed with regard to the research domain criteria framework.

Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology.

BACKGROUND: Most individuals exposed to a traumatic event do not develop post-traumatic stress disorder (PTSD), although many individuals may experience sub-clinical levels of post-traumatic stress symptoms (PTSS). There are notable individual differences in the presence and severity of PTSS among individuals who report seemingly comparable traumatic events. Individual differences in PTSS following exposure to traumatic events could be influenced by pre-trauma vulnerabilities for developing PTSS/PTSD. METHODS: Pre-trauma psychological, psychophysiological and personality variables were prospectively assessed for their predictive relationships with post-traumatic stress symptoms (PTSS). Police and firefighter trainees were tested at the start of their professional training (i.e., pre-trauma; n = 211) and again several months after exposure to a potentially traumatic event (i.e., post-trauma, n = 99). Pre-trauma assessments included diagnostic interviews, psychological and personality measures and two psychophysiological assessment procedures. The psychophysiological assessments measured psychophysiologic reactivity to loud tones and the acquisition and extinction of a conditioned fear response. Post-trauma assessment included a measure of psychophysiologic reactivity during recollection of the traumatic event using a script-driven imagery task. RESULTS: Logistic stepwise regression identified the combination of lower IQ, higher depression score and poorer extinction of forehead (corrugator) electromyogram responses as pre-trauma predictors of higher PTSS. The combination of lower IQ and increased skin conductance (SC) reactivity to loud tones were identified as pre-trauma predictors of higher post-trauma psychophysiologic reactivity during recollection of the traumatic event. A univariate relationship was also observed between pre-trauma heart rate (HR) reactivity to fear cues during conditioning and post-trauma psychophysiologic reactivity. CONCLUSION: The current study contributes to a very limited literature reporting results from truly prospective examinations of pre-trauma physiologic, psychologic, and demographic predictors of PTSS. Findings that combinations of lower estimated IQ, greater depression symptoms, a larger differential corrugator EMG response during extinction and larger SC responses to loud tones significantly predicted higher PTSS suggests that the process(es) underlying these traits contribute to the pathogenesis of subjective and physiological PTSS. Due to the low levels of PTSS severity and relatively restricted ranges of outcome scores due to the healthy nature of the participants, results may underestimate actual predictive relationships.

In vivo 6-thioguanine-resistant T cells from melanoma patients have public TCR and share TCR beta amino acid sequences with melanoma-reactive T cells.

In vivo hypoxanthine-guanine phosphoribosyltransferase (HPRT)-deficient T cells (MT) from melanoma patients are enriched for T cells with in vivo clonal amplifications that traffic between blood and tumor tissues. Melanoma is thus a model cancer to test the hypothesis that in vivo MT from cancer patients can be used as immunological probes for immunogenic tumor antigens. MT were obtained by 6-thioguanine (TG) selection of lymphocytes from peripheral blood and tumor tissues, and wild-type T cells (WT) were obtained analogously without TG selection. cDNA sequences of the T cell receptor beta chains (TRB) were used as unambiguous biomarkers of in vivo clonality and as indicators of T cell specificity. Public TRB were identified in MT from the blood and tumor of different melanoma patients. Such public TRB were not found in normal control MT or WT. As an indicator of T cell specificity for melanoma, the >2600 MT and WT TRB, including the public TRB from melanoma patients, were compared to a literature-derived empirical database of >1270 TRB from melanoma-reactive T cells. Various degrees of similarity, ranging from 100% conservation to 3-amino acid motifs (3-mer), were found between both melanoma patient MT and WT TRBs and the empirical database. The frequency of 3-mer and 4-mer TRB matching to the empirical database was significantly higher in MT compared with WT in the tumor (p=0.0285 and p=0.006, respectively). In summary, in vivo MT from melanoma patients contain public TRB as well as T cells with specificity for characterized melanoma antigens. We conclude that in vivo MT merit study as novel probes for uncharacterized immunogenic antigens in melanoma and other malignancies.