An investigation of attitudes and attentional biases in trichotillomania

Trichotillomania (TTM) is a body focussed repetitive behaviour (BFRB) characterised by the repetitive pulling out of one’s hair. It is a moderately new disorder having only been classified in 1987 and it is under-researched relative to other psychological disorders. This thesis investigates TTM by presenting a series of experiments designed to further understand attitudes towards, and attentional biases in, TTM. The experiments in this thesis address 3 central issues: stigmatising attitudes towards TTM; attentional bias pertaining to the experience of shame in TTM; and attentional bias towards hair-related stimuli in TTM. Experiment 1 investigated differences in ratings of stigma towards perceived controllable (TTM, compulsive skin-picking) and perceived uncontrollable (alopecia, psoriasis) hair-loss and skin-lesioning conditions in a TTM and control group. The main findings indicated that stigma ratings varied as a function of group: the public rated perceived controllable conditions with higher stigma than perceived uncontrollable conditions while TTM participants rated these conditions equally. Experiment 2 used a modified emotional Stroop task using shame-related words to investigate the affective correlate of shame in individuals with TTM and a control group. TTMs did not demonstrate different response latencies to shame-related words, relative to other word types or the control group, indicating no evidence of attentional bias towards shame-related linguistic stimuli. Experiments 3, 4 and 5 focussed specifically on disorder-stimuli (i.e., hair-related) linguistic stimuli in a series of lexical paradigms. Experiment 3 was a lexical decision task and Experiment 4 was a modified Stroop task: these paradigms investigated response latencies towards hair-related words in TTMs and a control group. The main findings for both experiments showed that TTMs do not demonstrate an attentional bias towards hair-related words, relative to other word types and the control group. Experiment 5 investigated higher-level judgements of hair-related words in a word rating task. The findings revealed a group-by-word-type interaction for arousal ratings: TTMs rated hair-related words higher in arousal than body image and neutral words, and these ratings were higher than those of the control group for hair-related words. No group-by-word-type interaction for valence ratings was found. This indicates that TTMs rate hair-related words as more arousing but not more positive or negative, than other word types, relative to individuals without TTM. Finally, Experiment 6 utilised a modified dot probe paradigm to investigate attentional bias towards hair-related images. Our findings showed that TTMs disengage more slowly from hair-related images at a longer stimulus duration compared to neutral images, relative to control participants. This evidence is consistent with an attentional bias characterised by maintained attention towards hair-related stimuli in individuals with TTM. In conclusion, this thesis has presented evidence indicating that TTM (and other BFRBs) are associated with higher public stigma ratings than comparable perceived uncontrollable conditions. Results have also shown an attentional bias towards hair-related images but not words. This represents an important contribution towards the understanding of the processing of disorder-related stimuli in TTM. This may have implications for the maintenance mechanisms potentially involved in the hair-pulling condition

A general role for TANGO1, encoded by MIA3, in secretory pathway organization and function

Complex machinery is required to drive secretory cargo export from the endoplasmic reticulum (ER), which is an essential process in eukaryotic cells. In vertebrates, the MIA3 gene encodes two major forms of transport and Golgi organization protein 1 (TANGO1S and TANGO1L), which have previously been implicated in selective trafficking of procollagen. Using genome engineering of human cells, light microscopy, secretion assays, genomics and proteomics, we show that disruption of the longer form, TANGO1L, results in relatively minor defects in secretory pathway organization and function, including having limited impacts on procollagen secretion. In contrast, loss of both long and short forms results in major defects in cell organization and secretion. These include a failure to maintain the localization of ERGIC53 (also known as LMAN1) and SURF4 to the ER–Golgi intermediate compartment and dramatic changes to the ultrastructure of the ER–Golgi interface. Disruption of TANGO1 causes significant changes in early secretory pathway gene and protein expression, and impairs secretion not only of large proteins, but of all types of secretory cargo, including small soluble proteins. Our data support a general role for MIA3/TANGO1 in maintaining secretory pathway structure and function in vertebrate cells

Pathogen disgust predicts stigmatization of individuals with mental health conditions

Both avoidance of individuals with cues of infectious illnesses and stigmatization of other types of individual (e.g., obese individuals) are hypothesized to reflect infectious disease avoidance. However, direct empirical tests of this hypothesis have been somewhat rare. Consequently, we tested for possible relationships between subscales of the Three Domain Disgust Scale and stigmatization of individuals with one of three mental health conditions (schizophrenia, skin-picking disorder, or sexual sadism disorder) in a sample of 117 participants. Scores on the pathogen disgust subscale of the Three Domain Disgust Scale were positively correlated with stigmatization of these mental health conditions. By contrast, scores on the sexual and moral disgust subscales of the Three Domain Disgust Scale were not significantly related to the stigmatization of mental health conditions. When analyzed separately, there were significant positive effects of pathogen disgust for skin picking and sexual sadism, but not schizophrenia. These results potentially implicate overgeneralization of infectious disease avoidance in the stigmatization of individuals with mental health conditions

Response to novel objects and foraging tasks by common marmoset (Callithrix Jacchus) female Pairs

Many studies have shown that environmental enrichment can significantly improve the psychological well-being of captive primates, increasing the occurrence of explorative behavior and thus reducing boredom. The response of primates to enrichment devices may be affected by many factors such as species, sex, age, personality and social context. Environmental enrichment is particularly important for social primates living in unnatural social groupings (i.e. same-sex pairs or singly housed animals), who have very few, or no, benefits from the presence of social companions in addition to all the problems related to captivity (e.g. increased inactivity). This study analyses the effects of enrichment devices (i.e. novel objects and foraging tasks) on the behavior of common marmoset (Callithrix jacchus) female pairs, a species that usually lives in family groups. It aims to determine which aspects of an enrichment device are more likely to elicit explorative behaviors, and how aggressive and stress-related behaviors are affected by its presence. Overall, the marmosets explored foraging tasks significantly longer than novel objects. The type of object, which varied in size, shape and aural responsiveness (i.e. they made a noise when the monkey touched them), did not affect the response of the monkeys, but they explored objects that were placed higher in the enclosure more than those placed lower down.Younger monkeys were more attracted to the enrichment devices than the older ones. Finally, stress-related behavior (i.e. scratching) significantly decreased when the monkeys were presented with the objects; aggressive behavior as unaffected. This study supports the importance of environmental enrichment for captive primates and shows that in marmosets its effectiveness strongly depends upon the height of the device in the enclosure and the presence of hidden food. The findings can be explained ifone considers the foraging behavior of wild common marmosets. Broader applications for the research findings are suggested in relation to enrichment

Early adolescent disclosure and parental knowledge regarding online activities: Social anxiety and parental rule-setting as moderators

Early adolescents spend a lot of time online, yet little is currently known about the links between parental rule-setting, adolescent disclosure about online activities, and whether social anxiety may interfere with these processes. Using a longitudinal sample of 526 adolescents (269 girls; Mage = 14.00) and their parents (79% mothers, Mage = 43.66), the results from the current study showed low correspondence between parental knowledge, adolescent disclosure, as well as parents’ and adolescents’ ratings of parental legitimacy to set boundaries about online activities. High social anxiety interacted with high adolescent-rated parental rule-setting in predicting the least disclosure about chatting with strangers and posting online content over time. Also, high social anxiety interacted with low parent-rated control to predict more adolescent disclosure about chatting with strangers and money spent online over time. Thus, social anxiety and parental rule-setting moderated the links between disclosure and knowledge for some early adolescent online activities. Our results conflict with the value typically placed on parental rule-setting in online contexts, at least for socially anxious adolescents

ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Deep Molecular Characterization of HIV-1 Dynamics under Suppressive HAART

In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0.042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P<10−6 AMOVA test; P = 0.001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P<10−6) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infection

The CCP4 suite: integrative software for macromolecular crystallography

The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.Jon Agirre is a Royal Society University Research Fellow (UF160039 and URF\R\221006). Mihaela Atanasova is funded by the UK Engineering and Physical Sciences Research Council (EPSRC; EP/R513386/1). Haroldas Bagdonas is funded by The Royal Society (RGF/R1/181006). Jose´ Javier Burgos-Ma´rmol and Daniel J. Rigden are supported by the BBSRC (BB/S007105/1). Robbie P. Joosten is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 871037 (iNEXTDiscovery) and by CCP4. This work was supported by the Medical Research Council as part of United Kingdom Research and Innovation, also known as UK Research and Innovation: MRC file reference No. MC_UP_A025_1012 to Garib N. Murshudov, which also funded Keitaro Yamashita, Paul Emsley and Fei Long. Robert A. Nicholls is funded by the BBSRC (BB/S007083/1). Soon Wen Hoh is funded by the BBSRC (BB/T012935/1). Kevin D. Cowtan and Paul S. Bond are funded in part by the BBSRC (BB/S005099/1). John Berrisford and Sameer Velankar thank the European Molecular Biology Laboratory–European Bioinformatics Institute, who supported this work. Andrea Thorn was supported in the development of AUSPEX by the German Federal Ministry of Education and Research (05K19WWA and 05K22GU5) and by Deutsche Forschungsgemeinschaft (TH2135/2-1). Petr Kolenko and Martin Maly´ are funded by the MEYS CR (CZ.02.1.01/0.0/0.0/16_019/0000778). Martin Maly´ is funded by the Czech Academy of Sciences (86652036) and CCP4/STFC (521862101). Anastassis Perrakis acknowledges funding from iNEXT (grant No. 653706), iNEXT-Discovery (grant No. 871037), West-Life (grant No. 675858) and EOSC-Life (grant No. 824087) funded by the Horizon 2020 program of the European Commission. Robbie P. Joosten has been the recipient of a Veni grant (722.011.011) and a Vidi grant (723.013.003) from the Netherlands Organization for Scientific Research (NWO). Maarten L. Hekkelman, Robbie P. Joosten and Anastassis Perrakis thank the Research High Performance Computing facility of the Netherlands Cancer Institute for providing and maintaining computation resources and acknowledge the institutional grant from the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport. Tarik R. Drevon is funded by the BBSRC (BB/S007040/1). Randy J. Read is supported by a Principal Research Fellowship from the Wellcome Trust (grant 209407/Z/17/Z). Atlanta G. Cook is supported by a Wellcome Trust SRF (200898) and a Wellcome Centre for Cell Biology core grant (203149). Isabel Uso´n acknowledges support from STFC-UK/CCP4: ‘Agreement for the integration of methods into the CCP4 software distribution, ARCIMBOLDO_LOW’ and Spanish MICINN/AEI/FEDER/UE (PID2021-128751NB-I00). Pavol Skubak and Navraj Pannu were funded by the NWO Applied Sciences and Engineering Domain and CCP4 (grant Nos. 13337 and 16219). Bernhard Lohkamp was supported by the Ro¨ntgen A˚ ngstro¨m Cluster (grant 349-2013-597). Nicholas Pearce is currently funded by the SciLifeLab and Wallenberg Data Driven Life Science Program (grant KAW 2020.0239) and has previously been funded by a Veni Fellowship (VI.Veni.192.143) from the Dutch Research Council (NWO), a Long-term EMBO fellowship (ALTF 609-2017) and EPSRC grant EP/G037280/1. David M. Lawson received funding from BBSRC Institute Strategic Programme Grants (BB/P012523/1 and BB/P012574/1). Lucrezia Catapano is the recipient of an STFC/CCP4-funded PhD studentship (Agreement No: 7920 S2 2020 007).Peer reviewe

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care