Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory.

BACKGROUND: Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS: Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS: Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS: Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.

Ape recognition of familiar human faces changed by time and COVID-19 face masks.

Reports of primates being able to recognise familiar humans are rare in the literature and tend to be regarded as anecdotal. The COVID-19 pandemic created two unique conditions facilitating the observation of spontaneous face recognition in zoo apes: i) lengthy gaps in contact with human visitors due to lockdowns and zoo closures, and ii) the wearing of face masks obscuring at least half the face of familiar individuals. Here, I report on the historical context of the familiarity between a primatologist and individual apes of two species, how those apes consistently showed recognition of this particular human over a time span of up to thirty years, how facial recognition was extended to family members, and how recognition persisted even when a significant portion of the face was obscured by a mask. This constitutes, to my knowledge, the first documented cases of recognition of familiar human faces changed by time and COVID-19 face masks in two great ape species. Although based on just two individuals, the documentation of this ability is important because it arose in a more naturalistic and spontaneous context compared to typical face processing research in which primates are tested with experimental stimuli in a laboratory setting. Implications for face processing theory and applications for the therapeutic utility of faces are discussed. These observations provide insight into the evolutionary origins of face recognition and, sitting at the interface of science and society, are of interest to a wide audience.

Design and Implementation of an Opt-Out, End-to-End, Preemptive DPYD Testing Program for Patients Planned for a Systemic Fluoropyrimidine.

PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record-based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non-fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.

Facial Expression of TIPI Personality and CHMP-Tri Psychopathy Traits in Chimpanzees (Pan troglodytes) : Evidence for Honest Signalling?

Honest signalling theory suggests that humans and chimpanzees can extract socially relevant information relating to personality from the faces of their conspecifics. Humans are also able to extract information from chimpanzees' faces. Here, we examine whether personality characteristics of chimpanzees, including measures of psychopathy, can be discerned based purely on facial morphology in photographs. Twenty-one chimpanzees were given naïve and expert personality ratings on the Ten Item Personality Inventory (TIPI) and the Chimpanzee Triarchic Model of Psychopathy (CHMP-Tri) before and following behavioural observations. Characteristics relating to openness, conscientiousness, extraversion, and disinhibition could be distinguished from the faces of chimpanzees. Individuals higher on disinhibition have lower scores on conscientiousness and emotional stability and higher scores on extraversion, while those higher on meanness have lower conscientiousness and agreeableness. Facial expressions are linked to personality traits present in the TIPI and CHMP-Tri models: the Relaxed Face and the Grooming Face were displayed more by chimpanzees higher on agreeableness, whereas the Compressed Lips Face was observed more in those individuals higher on boldness, and the Full Open Grin was displayed more by chimpanzees higher on extraversion but lower on emotional stability and conscientiousness. Facial expressions were also found to be associated with particular behavioural contexts, namely the Grooming Face in affiliative contexts and the Relaxed and Relaxed Open Mouth Faces in neutral contexts. Dominant chimpanzees display higher levels of boldness and more Compressed Lips Faces, Relaxed Open Mouth Faces, and Grooming Faces than subordinate individuals. These findings support and extend evidence for an honest signalling system and a personality structure shared between humans and chimpanzees. Future research could further explore how personality is conveyed through the face, perhaps through more than just singular aspects of character, and maybe reflecting what chimpanzees themselves are able to do.

Feasibility and Acceptability of Internet-Based Interpersonal Psychotherapy for Stress, Anxiety, and Depression in Prenatal Women: Thematic Analysis.

BACKGROUND: Prenatal mental health is a global health concern. Despite the far-reaching impact of prenatal mental health issues, many women do not receive the psychological care they require. Women in their childbearing years are frequent users of the internet and smartphone apps. Prenatal women are prime candidates for internet-based support for mental health care. OBJECTIVE: This study aimed to examine the feasibility and acceptability of internet-based interpersonal psychotherapy (IPT) for prenatal women. METHODS: Semistructured interviews were conducted with women who had received internet-based IPT modules with guided support as a component of a randomized controlled trial evaluating the scale-up implementation of a digital mental health platform (The Healthy Outcomes of Pregnancy and Postpartum Experiences digital platform) for pregnant women. Qualitative thematic analysis was used to explore and describe women's experiences. Data were analyzed for emerging themes, which were identified and coded. RESULTS: A total of 15 prenatal women were interviewed to examine their experiences and views on the feasibility and acceptability of internet-based IPT modules. Participants found the content informative and appreciated the ways in which the digital mental health platform made the IPT modules accessible to users. Participants voiced some differing requirements regarding the depth and the way information was presented and accessed on the digital mental health platform. The important areas for improvement that were identified were acknowledging greater depth and clarity of content, the need for sociability and relationships, and refinement of the digital mental health platform to a smartphone app. CONCLUSIONS: This study provides useful evidence regarding treatment format and content preferences, which may inform future development. It also provides research data on the feasibility and acceptability of web-based applications for prenatal mental health care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01901796; https://clinicaltrials.gov/ct2/show/NCT01901796.

Mirror self-recognition in gorillas (Gorilla gorilla gorilla): a review and evaluation of mark test replications and variants.

Mirror self-recognition (MSR), widely regarded as an indicator of self-awareness, has not been demonstrated consistently in gorillas. We aimed to examine this issue by setting out a method to evaluate gorilla self-recognition studies that is objective, quantifiable, and easy to replicate. Using Suarez and Gallup's (J Hum Evol 10:175-183, 1981) study as a reference point, we drew up a list of 15 methodological criteria and assigned scores to all published studies of gorilla MSR for both methodology and outcomes. Key features of studies finding both mark-directed and spontaneous self-directed responses included visually inaccessible marks, controls for tactile and olfactory cues, subjects who were at least 5 years old, and clearly distinguishing between responses in front of versus away from the mirror. Additional important criteria include videotaping the tests, having more than one subject, subjects with adequate social rearing, reporting post-marking observations with mirror absent, and giving mirror exposure in a social versus individual setting. Our prediction that MSR studies would obtain progressively higher scores as procedures and behavioural coding practices improved over time was supported for methods, but not for outcomes. These findings illustrate that methodological rigour does not guarantee stronger evidence of self-recognition in gorillas; methodological differences alone do not explain the inconsistent evidence for MSR in gorillas. By implication, it might be suggested that, in general, gorillas do not show compelling evidence of MSR. We advocate that future MSR studies incorporate the same criteria to optimize the quality of attempts to clarify the self-recognition abilities of gorillas as well as other species.

Limb preference and personality in donkeys (Equus asinus).

Interhemispheric laterality has often been linked to different behavioural styles. This study investigates the link between limb preference and personality in donkeys. The sample consisted of 47 donkeys (Equus asinus), 30 males and 17 females. Limb preference was determined using observation of the leading limb in a motionless posture and personality was measured using the Donkey Temperament Questionnaire (French, J. M. (1993). Assessment of donkey temperament and the influence of home environment. Applied Animal Behaviour Science, 36(2), 249-257. doi:10.1016/0168-1591(93)90014-G) completed by the donkeys' keepers. A Principal Component Analysis obtained two components: Agreeableness and Extraversion. Age showed a positive relationship with Agreeableness, echoing trends in humans Donkeys did not show a population-level preference towards either side. Limb preference significantly predicted the trait difficult to handle: donkeys with a preference to keep the right foot forward when motionless were harder to handle. This study presents the first investigation into limb preference and personality in donkeys, although more research is needed to clarify whether there is a population-level limb preference bias in donkeys, and the relationship between limb preference and Agreeableness.

Personality and behavioral changes in Asian elephants (Elephas maximus) following the death of herd members.

Elephants are highly social beings with complex individual personalities. We know that elephants have a general interest in death, investigating carcasses, not just limited to kin; however, research does not explore in depth whether individuals change their behavior or personality following traumatic events, such as the death of a conspecific. Within a captive herd of Asian elephants (Elephas maximus) housed at Chester Zoo, UK, we measured social behavior and proximity and personality using the Ten-Item Personality Inventory, and found age-related and relationship-related changes in both behavior and personality following the deaths of herd members. Overall, the herd spent less time socializing and engaging in affiliative behaviors following the death of the adult female when compared to baseline data, yet spent more time engaging in these behaviors after the death of two calves. The death of the central female had a dramatic impact on her infant calf, resulting in increasingly withdrawn behavior, yet had the opposite effect on her adult daughter, who subsequently established a more integrated role within the herd. Emotional Stability fell in the motherless calf but rose in an adult female, who had lost her adult daughter, but had a new calf to care for. We suggest that the greater impact on the behavior and personality of surviving herd members following the deaths of calves, compared to an adult member, attests to the significance of the unifying role played by calves within an elephant herd.

There is no other monkey in the mirror for spider monkeys (Ateles geoffroyi).

Mirror self-recognition (MSR), usually considered a marker of self-awareness, occurs in several species and may reflect a capacity that has evolved in small incremental steps. In line with research on human development and building on previous research adopting a gradualist framework, we categorized the initial mirror responses of naïve spider monkeys (Ateles geoffroyi) according to four levels. We compared social, exploratory, contingent and self-exploratory responses to a mirror and faux mirror during three short trials. If spider monkeys respond as most monkey species, we predicted they would perform at level 0, mainly showing social behavior toward their mirror-image. However, because spider monkeys show enhancement of certain cognitive skills comparable to those of great ape species, we predicted that they would perform at level 1a (showing exploratory behavior) or 1b (showing contingent behavior). GLMMs revealed that monkeys looked behind and visually inspected the mirror significantly more in the mirror than the faux mirror condition. Although the monkeys engaged in contingent body movements at the mirror, this trend was not significant. Strikingly, they showed no social behaviors toward their mirror-image. We also measured self-scratching as an indicator of anxiety and found no differences in frequencies of self-scratching between conditions. Therefore, in contrast to most findings on other species, spider monkeys did not treat their image as another monkey during their initial exposure to the mirror. In fact, they reached at least level 1a within minutes of mirror exposure. These responses recommend spider monkeys as good candidates for further explorations into monkey self-recognition. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Video-mediated behavior in gorillas (gorilla gorilla gorilla): A stage in the development of self-recognition in a juvenile male?

The anomalous position of gorillas (Gorilla gorilla gorilla) in the capacity for self-recognition remains puzzling. The standard measure of self-recognition is Gallup's (1970) mark test that assesses an individual's ability to recognize its altered image in a mirror following the application of paint marks to visually inaccessible areas. Here, the results of a small-scale pilot study are presented, utilizing video playback through a TV monitor, to examine behavioral differences indicative of developing self-recognition. The behaviors of 4 Western lowland gorillas at Bristol Zoo, United Kingdom, were observed while watching a TV screen during 5 conditions: blank screen, white noise interference, footage of unfamiliar gorillas, self previously recorded, and self-live. Differences were predicted in the frequency of the gorillas' observed behaviors when viewing each of the conditions: specifically, that there would be more visual inspection, contingent body and facial movements, and self-exploration in the self-recorded and self-live conditions compared with the other conditions. These predictions were partially supported. No agonistic or fear responses were observed, and self-exploration was only seen in the self-live condition. During live playback, contingency-checking movements and self-exploration of the mouth were observed, particularly in the youngest gorilla, providing important video evidence of a close parallel to the mouth exploratory behavior witnessed in self-recognizing chimpanzees. On the basis of these preliminary findings of differentiated spontaneous behaviors, a tentative framework is proposed for categorizing gorillas according to levels of developing self-recognition along a continuum. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Complex Sociality of Wild Chimpanzees Can Emerge from Laterality of Manual Gestures.

Humans are strongly lateralized for manual gestures at both individual and population levels. In contrast, the laterality bias in primates is less strong, leading some to suggest that lateralization evolved after the Pan and Homo lineages diverged. However, laterality in humans is also context-dependent, suggesting that observed differences in lateralization between primates and humans may be related to external factors such as the complexity of the social environment. Here we address this question in wild chimpanzees and examine the extent to which the laterality of manual gestures is associated with social complexity. Right-handed gestures were more strongly associated with goal-directed communication such as repair through elaboration in response to communication failure than left-handed gestures. Right-handed gestures occurred in evolutionarily urgent contexts such as in interactions with central individuals in the network, including grooming reciprocity and mating, whereas left-handed gestures occurred in less-urgent contexts, such as travel and play. Right-handed gestures occurred in smaller parties and in the absence of social competition relative to left-handed gestures. Right-handed gestures increased the rate of activities indicating high physiological arousal in the recipient, whereas left-handed gestures reduced it. This shows that right- and left-handed gestures differ in cognitive and social complexity, with right-handed gestures facilitating more complex interactions in simpler social settings, whereas left-handed gestures facilitate more rewarding interactions in complex social settings. Differences in laterality between other primates and humans are likely to be driven by differences in the complexity of both the cognitive skills underpinning social interactions and the social environment.

Quality of Explanation as an Indicator of Fraction Magnitude Understanding.

Students' explanations of their mathematical thinking and conclusions have become a greater part of the assessment landscape in recent years. With a sample of 71 fourth-grade students at risk for mathematics learning disabilities, we investigated the relation between student accuracy in comparing the magnitude of fractions and the quality of students' explanations of those comparisons, as well as the relation between those measures and scores on a criterion test: released fraction items from the National Assessment of Educational Progress. We also considered the extent to which reasoning and language contribute to the prediction. Results indicated a significant moderate correlation between accuracy and explanation quality. Commonality analyses indicated that explanation quality accounts for little variance in National Assessment of Educational Progress scores beyond what is accounted for by traditional measures of magnitude understanding. Implications for instruction and assessment are discussed.

Internet-based interpersonal psychotherapy for stress, anxiety, and depression in prenatal women: study protocol for a pilot randomized controlled trial.

BACKGROUND: Psychological distress, defined as depression, anxiety and perceived stress, during pregnancy is common, with 15-25% of women experiencing clinically significant levels of such distress. Despite the far-reaching impact of prenatal psychological distress on mothers and their children, and that women are receptive to screening, few providers routinely screen for prenatal psychological distress and less than one in five women will receive the mental health care that they require. There is a lack of certainty regarding the most effective treatments for prenatal psychological distress. No online interpersonal psychotherapy (IPT) trials have been conducted that focus on improving psychological distress in prenatal women. The purpose of this pilot randomized controlled trial is to evaluate the perspectives of pregnant women on the feasibility and acceptability of online IPT (e-IPT) delivered during pregnancy. METHODS: A pilot randomized controlled trial design with repeated measures will evaluate the feasibility and acceptability of e-IPT for pregnant women compared to routine prenatal care. Qualitative interviews with 15-30 individuals in the intervention group will provide further data on the feasibility and acceptability of the intervention. Assessment of feasibility will include the ease of accessing and completing the intervention. Women will also be asked about what barriers there were to starting and completing the e-IPT. Assessment of acceptability will inquire about the perception of women regarding the intervention and its various features. A sample size of 160 consenting pregnant women aged 18 years and older will be enrolled and randomized into the experimental (e-IPT) or control (routine care) condition. The secondary outcome measures include: depression, anxiety and stress symptoms; self-efficacy; self-mastery; self-esteem; relationship quality (spouse, immediate family members); coping; and resilience. All participants will complete the aforementioned measures at baseline during pregnancy (T1), 3 months postrandomization (T2), at 8 months of pregnancy (T3), and 3 months postpartum (T4). DISCUSSION: The results of this pilot randomized controlled trial will provide data on the feasibility and acceptability of the intervention and identify necessary adaptations. This study will allow for optimization of full trial processes and inform the evaluation strategy, including sample size calculations for the full randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01901796. Registered on 18 December 2014.

Neuroticism and extraversion mediate the relationship between having a sibling with developmental disabilities and anxiety and depression symptoms.

Background Children growing up with a sibling with disabilities report higher levels of depression and anxiety symptoms as adults. Here, we examined whether personality characteristics also play a part in mediating this relationship. Method We tested for differences in personality traits between 132 individuals who have a sibling with developmental disabilities and 132 closely matched comparisons. Results Differences in Big Five factors of personality were demonstrated across the disability groups and between the disability groups and the comparisons, especially in Extraversion, Neuroticism and Openness. Individuals growing up alongside a sibling with developmental disabilities have a higher tendency to experience anxiety and depression symptoms, and this research is the first demonstration that personality traits mediate this relationship. Specifically, Neuroticism is a strong mediator of anxiety while both Neuroticism and Extraversion contribute mediating effects toward the development of depression. Limitations Our study made use of self-report methodology which, although having recognized limitations, is more reliable than parental reports. Given the cross-sectional nature of our design, we were not able to examine pre-existing developmental factors that may have influenced the participant's propensity to particular personality traits and affective disorders. However, we obtained a large sample and closely matched participants to examine differences between those with a sibling with disabilities and those without. Conclusions As such, differences in personality traits have important implications for the understanding and treatment of siblings presenting with anxiety and depression symptoms. We recommend that intervention should target those high in Neuroticism among individuals who have a sibling with disabilities, and that more social support is put in place for siblings to mitigate their tendency towards introversion and buffer them against psychological maladjustment.

Perceived Parenting Styles Fail to Mediate Between Anxiety and Attachment Styles in Adult Siblings of Individuals with Developmental Disabilities.

Adult siblings of individuals with developmental disabilities often experience higher levels of anxiety than individuals in the general population. The present study tested whether perceived parenting could mediate the relationship between attachment styles and anxiety in the sibling group compared to a control group. Little association was found between perceived parenting and attachment styles or anxiety for the siblings but there were robust and expected findings for the control. Adult attachment-related-anxiety was a significant unique predictor of anxiety in the sibling group but there was no mediational role for perceived parenting. Conversely, the majority of parenting styles significantly mediated the relationship between attachment and anxiety in the control. Implications for the atypical findings in the sibling group are discussed.

Anxiety and depression symptomatology in adult siblings of individuals with different developmental disability diagnoses.

Factors predicting the emotional well-being of adult siblings of those with developmental disability (DD) remain under-researched. In this study adult siblings of individuals with Down's syndrome (DS), autism (ASD), Prader-Willi syndrome (PWS) and those with DD but with unknown aetiology (DUA) were compared with each other and a closely-matched control group to ascertain if sibling disability type made a difference to anxiety and/or depression levels. Also considered was the interactive effect of gender, age, parental and sibling educational attainment levels, socio-economic status and birth order on anxiety and depression outcomes. With the exception of siblings of those with DS, adult siblings of those with ASD, PWS and DUA reported significantly higher levels of anxiety and depression than the control group. There were some predictive effects of the demographic variables upon anxiety and depression but none common to all disability types and no moderating effects of demographic factors were found. Consequently other solutions must be found as to why this important group of people have elevated rates of anxiety and depression in comparison to the general population.

"A thrill of extreme magnety": Robert E. Gross and the beginnings of cardiac surgery.

Seventy-five years ago, a 7-year-old girl underwent the first successful ligation of a patent ductus arteriosus. This procedure transformed her health and was a milestone in the development of cardiac surgery. The operation was performed by Dr. Robert E. Gross, then the surgical chief resident at Boston Children's Hospital, who went on to have a distinguished career in pediatric surgery. The patient is now a great-grandmother and the oldest known survivor of cardiac surgery.

Bridging cardiogenic shock patients with short-term ventricular support at a community hospital to long-term ventricular support at a tertiary hospital.

BACKGROUND: Patients in cardiogenic shock require immediate circulatory support. Outcomes of patients who underwent short-term ventricular assist device (STVAD) implantation in a community hospital (CH) as a bridge to a long-term VAD (LTVAD) were compared with those who received both implants at the same tertiary hospital (TH). METHODS: Data were retrospectively reviewed for patients with a STVAD who were bridged to a LTVAD in a TH from 1997 to 2010. We studied outcomes and survival censored for cardiac transplantation. RESULTS: Thirty-seven patients (73% male) were identified. Mean age was 52 ± 16 years, 30% were diabetic, and 65% had intra-aortic balloon pump support. Reasons for STVAD implantation were an acute myocardial infarction, 38%; post-cardiotomy, 38%, decompensated chronic heart failure, 19%; and others, 5%. A STVAD was implanted in a CH in 20 patients (54%), and they had fewer cardiovascular risk factors than those whose STVAD was implanted at the TH. All patients at the CH were at Interagency Registry for Mechanically Assisted Circulatory Support 1 compared with 71% at the TH (p = 0.014). Patients from the CH tended to die sooner after LTVAD implant, although long-term survival was similar. At the 1-year follow-up, 65% from the CH were alive or had received a transplant vs 60% from the TH. CONCLUSION: Patients with cardiogenic shock in whom a STVAD was implanted in a CH and then were bridged to a LTVAD in a TH had similar long-term survival as those bridged to LTVAD at the TH.

Ventricular assist device support as a bridge to heart transplantation in patients with giant cell myocarditis.

AIMS: Giant cell myocarditis (GCM) carries a poor prognosis and many patients require end-stage therapies. This study sought to determine the outcome of patients bridged with ventricular assist devices (VAD) to orthotopic heart transplantation (OHT). METHODS AND RESULTS: A retrospective data collection of all patients with GCM was performed. Diagnosis was determined by endomyocardial or explanted heart biopsy. Eight patients were found, but two of those patients went directly to OHT and were excluded. The remaining six patients received VADs, and these patients, aged 44 ± 18 years, were included. Five of the six patients were bridged with biventricular support and one patient was supported by left ventricular assist device (LVAD) alone. Two patients died on device support. Four patients were bridged to OHT 77 ± 42 days after device implantation. All four patients bridged with a VAD are alive, with a mean follow-up of 5.7 ± 4.1 years. Two patients were found to have recurrent GCM in the transplanted heart and were treated successfully with immunosuppression. Three patients had high grade (2R) rejection at 66 ± 52 days post-OHT. Cardiac function was preserved in all patients, and only one patient had cardiac allograft vasculopathy. CONCLUSION: Patients with end-stage GCM can be successfully bridged with VADs to OHT with very good post-OHT survival. The proper immunosuppressive regimen for this group needs further investigation given the frequency of rejection and GCM recurrence.

Amino acid substitutions within the 2C coding sequence of Theiler's Murine Encephalomyelitis virus alter virus growth and affect protein distribution.

Theiler's murine encephalomyelitis virus (TMEV) was used to investigate the distribution of P2 proteins in host cells and examine the effect of amino acid substitutions in conserved residues of the 2C protein on virus growth. The distribution of viral proteins 2B, 2C and 2BC with marker proteins of the endoplasmic reticulum (ER) and/or Golgi suggest an association with membranes of the secretory pathway. Similar results were obtained for truncated 2C and 2BC proteins with C-terminal deletions suggesting that the N-terminal region of the 2C protein is important in dictating distribution patterns. The significance of the high degree of conservation of this 2C region throughout the Picornaviridae was investigated by substituting conserved amino acid residues for alanine to create six mutant strains. Substitution mutations E(8)A, W(18)A and W(29)A abolished the ability of the virus to induce cytopathic effect (CPE) in BHK-21 cells. K(14)A, R(4)A and I(23)A delayed the onset and progression of CPE compared to the wild-type (WT) virus, and decreased virus yield. Immunofluorescence analysis of cells transiently expressing mutant 2C proteins revealed that the distribution of 2C was affected by substituting K(14), W(18) and I(23) for alanine indicating that specific conserved residues in 2C dictate protein distribution and virus growth.