Phenotypic and Genetic Variation in the Susceptibility of Haemophilus influenzae Type b to Antibodies to Somatic Antigens

Haemophilus influenzae type b (H.i.b) has been investigated with respect to phenotypic and genetic variations resulting in differential susceptibility to bactericidal antibody. Previous studies had shown that after growth in infected rats or in dialysate of rat serum, H.i.b strain Eag became more resistant to the bactericidal activity of antisomatic antibody. We now report that a similar phenotypic shift occurs when strain Eag is incubated with dialysate of human serum, that the increased resistance is to antibodies against determinants in the lipopolysaccharide not for the somatic antigens generally, and that most strains of H.i.b undergo the shift.To assess genetic differences in exposed antigens, a panel of 13 H.i.b isolates from cerebrospinal fluid were analyzed with cross-adsorbed antisera. Seven different patterns were found that could be accounted for through the variable expression of six antigens. These ranged from infrequent (found on 1:13 strains) to common (10:13 strains). At least four were somatic rather than capsular determinants; the most common (antigen 1) was contained in lipopolysaccharide.The epidemiologic relevance of the genetic variations was explored using pairs of isolates from two children who had had two documented infections with H.i.b. In both cases the isolates varied in somatic antigen expression. The strains from one patient differed in the expression of antigen 1. The isolates from the other were indistinguishable in sub-typing for the six classified antigens, but differed in the expression of an additional antigen identified by use of the patient's serum.     

Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation

Prenatal exposure of the brain to environmental insult causes different neurological symptoms and behavioral outcomes depending on the time of exposure. To examine the cellular bases for these differences, we exposed rhesus macaque fetuses to x‐rays during early gestation (embryonic day [E]30–E42), i.e., before the onset of corticogenesis, or in midgestation (E70–E81), when superficial cortical layers are generated. Animals were delivered at term (～E165), and the size and cellular composition of prefrontal association cortex (area 46) examined in adults using magnetic resonance imaging (MRI) and stereologic analysis. Both early and midgestational radiation exposure diminished the surface area and volume of area 46. However, early exposure spared cortical thickness and did not alter laminar composition, and due to higher cell density, neuron number was within the normal range. In contrast, exposure to x‐rays at midgestation reduced cortical thickness, mainly due to elimination of neurons destined for the superficial layers. A cell‐sparse gap, observed within layer III, was not filled by the later‐generated neurons destined for layer II, indicating that there is no subsequent replacement of the lost neurons. The distinct areal and laminar pathology consequent to temporally segregated irradiation is consistent with basic postulates of the radial unit hypothesis of cortical development. In addition, we show that an environmental disturbance inflicted in early gestation can induce subtle cytoarchitectonic alterations without loss of neurons, such as those observed in schizophrenia, whereas midgestational exposure causes selective elimination of neurons and cortical thinning as observed in some forms of mental retardation and fetal alcohol syndrome. J. Comp. Neurol. 521:1040–1053, 2013. © 2012 Wiley Periodicals, Inc.     

Inactivation of contraction as a determinant of the length-active tension relation in heart muscle of the cat

In isometrically contracting isolated cat papillary muscles, the mechanism determining the reduction in active tension (P) at lengths (L) below the optimal length (L_max) for maximal tension development (P_max) was studied. Increasing / _– ^– Ca^2+– / _–o ^max from 1.25 to 5 mM, paired electrical stimulation and caffeine augmented P_max by 77,61 and 23% respectively, as well as the tension developed at any given length on the ascending limb of the lengthactive tension relation. To see whether below L_max the degree of activation is dependent on length, these length-active tension relations were expressed as P/P_max relative to L/L_max where P_max and L_max in each inotropic state was 100%. These normalized Iength-active tension relations were not altered by different / _– ^– Ca _– ^2+– /_o, but shifted upward and to the left by caffeine and paired stimulation. The effects of elevating / _– ^– Ca _– ^2+– /_o on the length-active tension relation suggests that restoring forces and fixed internal loads are not an important factor in decreasing active tension at short lenghts. The effects of caffeine and paired stimulation support the view that in cardiac muscle inactivitation of contraction is a major factor determining the fall in active tension at decreasing length.     

Public self-awareness and withdrawal from social interactions

Women high and low in social self-efficacy participated in a social interaction either under conditions of heightened public self-awareness or in a control condition. The self-awareness manipulation increased self-focused attention and self-evaluation, but only among low-efficacy subjects. Low-efficacy subjects withdrew from the interaction more quickly than did high-efficacy subjects, but only when self-awareness was heightened. Both groups of low-efficacy subjects believed their partners would not like them, and the partners did indeed like these subjects less than the high-efficacy women. These results suggest that low-efficacy women are distinguished by a number of cognitive factors, even in the absence of self-directed attention. Faced with social scrutiny, these individuals engage in a perservative self-evaluation process, which ultimately leads to social withdrawal. The results are interpreted from the perspective of Ingram's (1990) interaction model of self-directed attention.This research was supported by a grant from the Social Sciences and Humanities Research Council of Canada.     

Inflammation-induced changes in rostral ventromedial medulla mu and kappa opioid receptor mediated antinociception

Acute microinjection of mu-, delta-, or kappa-opioid receptor (MOPr, DOPr, KOPr) agonists into the rostral ventromedial medulla (RVM) produces antinociception. Thermal antinociception produced by MOPr and DOPr agonists is potentiated during inflammation [Hurley RW, Hammond DL. The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation. J Neurosci 2000;20:1249-59]. Whether this potentiation extends to other stimulus modalities or to KOPr agonists is unknown. To examine these issues, rats received a unilateral intraplantar injection of complete Freund's adjuvant (CFA). Antinociception produced by RVM infusion of the KOPr agonist, U69593, and the MOPr agonist, DAMGO, was tested 4h-2 weeks thereafter. Thermal paw withdrawal latencies (PWLs) were assessed using the Hargreaves method. Mechanical thresholds were determined with the Von Frey and Randall-Selitto method. PWLs of the inflamed paw were reduced 4h-2 weeks after CFA injection. Infusion of either U69593 or DAMGO increased PWLs in CFA treated rats. A bilateral enhancement of the response to both agonists was observed 2 weeks relative to 4h post-CFA injection. Mechanical thresholds of the inflamed paw were decreased for >2 weeks post-CFA injection. Infusion of either agonist elevated thresholds of the inflamed and non-inflamed paws of CFA-treated rats. The magnitude of these effects was greater 2 weeks post-CFA injection for DAMGO and increased progressively for U69593. These data demonstrate that RVM infusion of MOPr or KOPr agonists attenuates CFA-evoked thermal and tactile allodynia and that these effects increase during prolonged inflammation. The augmented response of the non-inflamed paw to agonists suggests that inflammation induces centrally-mediated neuroplastic changes which enhance MOPr- and KOPr-mediated antinociception.     

Poster 40: Comparison of constraint-induced language therapy and traditional therapy in the rehabilitation of chronic aphasia: preliminary findings

Objectives: To compare constraint-induced language therapy (CILT) to a more traditional multimodality intervention for rehabilitation of chronic aphasia. Design: Nonrandomized control trial, within-subject comparisons. Setting: Outpatient rehabilitation. Participants: 9 subjects with chronic nonfluent aphasia >2 years poststroke. Intervention: 2 groups (n=4) were treated using key CILT principles: massed practice, constraint of other communication modalities, and forced use of language through the application of visual barriers in a supported environment; 2 groups (n=5) were treated using a traditional approach, which encouraged all modes of communication: verbal and nonverbal. Both groups received treatment 3h/d, 4d/wk for 2 consecutive weeks. Main Outcomes Measures: Western Aphasia Battery, Boston Naming Test, Action Naming Test, and linguistic analyses. Results: Although participants in both groups evinced positive outcomes posttreatment, CILT subjects showed increased performance on more measures than the traditional subjects. Conclusions: Findings support the notion that persons with chronic nonfluent aphasia may make substantial, measurable change in language after intensive CILT. Progress observed in both groups suggests intensity may be an important factor in the positive outcome for both conditions.     

Optimizing the human learnability of abstract network representations

Precisely how humans process relational patterns of information in knowledge, language, music, and society is not well understood. Prior work in the field of statistical learning has demonstrated that humans process such information by building internal models of the underlying network structure. However, these mental maps are often inaccurate due to limitations in human information processing. The existence of such limitations raises clear questions: Given a target network that one wishes for a human to learn, what network should one present to the human? Should one simply present the target network as-is, or should one emphasize certain parts of the network to proactively mitigate expected errors in learning? To investigate these questions, we study the optimization of network learnability in a computational model of human learning. Evaluating an array of synthetic and real-world networks, we find that learnability is enhanced by reinforcing connections within modules or clusters. In contrast, when networks contain significant core–periphery structure, we find that learnability is best optimized by reinforcing peripheral edges between low-degree nodes. Overall, our findings suggest that the accuracy of human network learning can be systematically enhanced by targeted emphasis and de-emphasis of prescribed sectors of information.

From a young age, humans demonstrate the capacity to learn the relationships between concepts (1–3). During the learning process, humans are exposed to discrete chunks of information that combine and interconnect to form cognitive maps that can be represented as complex networks (4–9). These chunks of information often appear in a natural sequential order, such as words in language, notes in music, and abstract concepts in stories and classroom lectures (10–14). Further, these sequences are encoded in the brain as networks, with links between items reflecting observed transitions (see refs. 15–18 for empirical studies and 19 for a recent review). Broadly, the fact that many different types of information exhibit temporal order (and therefore network structure) motivates investigations into the processes that underlie the human learning of transition networks (8, 19, 20).To understand the network-learning process, recent studies have investigated how humans internally construct abstract representations of associations (21–23). Using a variety of approaches, from computational models to artificial neural networks, such studies have consistently found that the mind builds network representations by integrating information over time. Such integration enables humans to compress exact sequences of experienced events into broader, but less precise, representations of context (24). These mental representations allow learners to make better generalizations about new information, at the cost of accuracy (22). Here, we focus on one particular modeling approach that accounts for the temporal integration and inaccuracies inherent in human learning. In particular, we build upon a maximum-entropy model, which posits that the mind learns a network representation of the world in a manner guided by a tradeoff between accuracy and complexity (21, 25). Specifically, in order to conserve mental resources, humans will tend to reduce the complexity of their representations at the cost of accuracy by allowing for errors during the learning process.While inaccuracies in human learning can aid flexibility across contexts, they present fundamental obstacles for the human comprehension of transition networks. Thus, a clear question emerges: What strategies should be employed to most effectively communicate the structure of a network to an inaccurate human learner? Prior studies of animal communication and behavior have demonstrated the utility of exaggerating the presentation of certain signals to receivers in offsetting erroneous information processing (26, 27). Similarly, one could imagine that, by emphasizing some features of a network over others, one may be able to correct for errors in human learning. Such an approach of targeted modulation of emphasis may be helpful not only in learning a whole network, but also in optimally learning particularly challenging parts of a network. In fact, humans show consistent difficulties in learning certain motifs in networks, such as the connections between modules (21, 28–30). Taken together, these observations suggest that disproportionately weighting specific network features that are difficult to learn may facilitate human network learning.     

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy,But Not Combination Therapy

BackgroundFor patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making.Materials and MethodsPatients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS).ResultsIn total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS.ConclusionThis single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.     

Widening or narrowing inequalities? The equity implications of digital tools to support COVID‐19 contact tracing: A qualitative study

BackgroundAs digital tools are increasingly used to support COVID‐19 contact tracing, the equity implications must be considered. As part of a study to understand the public''s views of digital contact tracing tools developed for the national ‘Test and Protect’ programme in Scotland, we aimed to explore the views of groups often excluded from such discussions. This paper reports on their views about the potential for contact tracing to exacerbate inequalities.MethodsA qualitative study was carried out; interviews were conducted with key informants from organizations supporting people in marginalized situations, followed by interviews and focus groups with people recruited from these groups. Participants included, or represented, minority ethnic groups, asylum seekers and refugees and those experiencing multiple disadvantage including severe and enduring poverty.ResultsA total of 42 people participated: 13 key informants and 29 members of the public. While public participants were supportive of contact tracing, key informants raised concerns. Both sets of participants spoke about how contact tracing, and its associated digital tools, might increase inequalities. Barriers included finances (inability to afford smartphones or the data to ensure access to the internet); language (digital tools were available only in English and required a degree of literacy, even for English speakers); and trust (many marginalized groups distrusted statutory organizations and there were concerns that data may be passed to other organizations). One strength was that NHS Scotland, the data guardian, is seen as a generally trustworthy organization. Poverty was recognized as a barrier to people''s ability to self‐isolate. Some participants were concerned about giving contact details of individuals who might struggle to self‐isolate for financial reasons.ConclusionsThe impact of contact tracing and associated digital tools on marginalized populations needs careful monitoring. This should include the contact tracing process and the ability of people to self‐isolate. Regular clear messaging from trusted groups and community members could help maintain trust and participation in the programme.Patient and Public ContributionOur patient and public involvement coapplicant, L. L., was involved in all aspects of the study including coauthorship. Interim results were presented to our local Public and Patient Involvement and Engagement Group, who commented on interpretation and made suggestions about further recruitment.