Characterisation of immune responses to varicella vaccination in relation to clinical outcome

PhDThis thesis examines both humoral and cellular adaptive immune responses to varicella vaccination (up to 18 months post immunisation), in an ethnically diverse population of healthcare workers. Using two parameters of humoral immunity at six weeks post first vaccination; (avidity readings 60%, and a TRFIA reading 400mIU/mL) a cut-off of 130mIU/mL was defined for a more sensitive in house immuno assay (TRFIA), in this vaccinated adult population. Using these cut-offs, three patterns of antibody responses were identified; primary responders who seroconverted following vaccination, secondary responders who had pre-existing immunity and subjects who responded poorly to vaccination. Demographic and immunological characteristics of each subset were examined. An association between black ethnicity and lower antibody titre to vaccination in primary responders was identified, whilst Caucasians were more likely to have a history and pre-existing immunity, in keeping with the epidemiology of chickenpox in temperate climates. The follow-up study revealed that affinity maturation to VZV can take longer than 18 months in response to vaccination. At follow-up, 25% of subjects recruited at this time point were seronegative by TRFIA. Seroconversion after two doses of vaccine and a TRFIA titre of <500mIU/ml after two doses were significantly associated with waning antibody titre over time. Positive IFN- ELISPOT responses at 18 months did not necessarily correspond with TRFIA seropositive status.

Retention of Female Faculty Members

The recruitment and the retention of female undergraduate and graduate students into engineering courses is discussed. A similar challenge lies in recruiting female faculty member from the limited pool of candidates in several fields at most universities. It is found that about half the females who were hired did not stay at the university. It is suggested that programs should be introduced to encourage mentoring and career development as such improvements would benefit all faculty members both female and male

Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis

Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1−/− mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1−/− multiciliated ependymal cells and human PCM1−/− retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1−/− RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1−/− ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types

Comparison of clinical geneticist and computer visual attention in assessing genetic conditions

Artificial intelligence (AI) for facial diagnostics is increasingly used in the genetics clinic to evaluate patients with potential genetic conditions. Current approaches focus on one type of AI called Deep Learning (DL). While DL- based facial diagnostic platforms have a high accuracy rate for many conditions, less is understood about how this technology assesses and classifies (categorizes) images, and how this compares to humans. To compare human and computer attention, we performed eye-tracking analyses of geneticist clinicians (n = 22) and non-clinicians (n = 22) who viewed images of people with 10 different genetic conditions, as well as images of unaffected individuals. We calculated the Intersection-over-Union (IoU) and Kullback–Leibler divergence (KL) to compare the visual attentions of the two participant groups, and then the clinician group against the saliency maps of our deep learning classifier. We found that human visual attention differs greatly from DL model’s saliency results. Averaging over all the test images, IoU and KL metric for the successful (accurate) clinician visual attentions versus the saliency maps were 0.15 and 11.15, respectively. Individuals also tend to have a specific pattern of image inspection, and clinicians demonstrate different visual attention patterns than non-clinicians (IoU and KL of clinicians versus non-clinicians were 0.47 and 2.73, respectively). This study shows that humans (at different levels of expertise) and a computer vision model examine images differently. Understanding these differences can improve the design and use of AI tools, and lead to more meaningful interactions between clinicians and AI technologies

A randomised controlled trial of positive memory training for the treatment of depression within schizophrenia

Abstract Background: Depression is highly prevalent within individuals diagnosed with schizophrenia, and is associated with an increased risk of suicide. There are no current evidence based treatments for low mood within this group. The specific targeting of co-morbid conditions within complex mental health problems lends itself to the development of short-term structured interventions which are relatively easy to disseminate within health services. A brief cognitive intervention based on a competitive memory theory of depression, is being evaluated in terms of its effectiveness in reducing depression within this group. Methods/Design: This is a single blind, intention-to-treat, multi-site, randomized controlled trial comparing Positive Memory Training plus Treatment as Usual with Treatment as Usual alone. Participants will be recruited from two NHS Trusts in Southern England. In order to be eligible, participants must have a DSM-V diagnosis of schizophrenia or schizo-affective disorder and exhibit at least a mild level of depression. Following baseline assessment eligible participants will be randomly allocated to either the Positive Memory Training plus Treatment as Usual group or the Treatment as Usual group. Outcome will be assessed at the end of treatment (3-months) and at 6-month and 9-month post randomization by assessors blind to group allocation. The primary outcome will be levels of depression and secondary outcomes will be severity of psychotic symptoms and cost-effectiveness. Semi-structured interviews will be conducted with all participants who are allocated to the treatment group so as to explore the acceptability of the intervention. Discussion: Cognitive behaviour therapy is recommended for individuals diagnosed with schizophrenia. However, the number of sessions and length of training required to deliver this intervention has caused a limit in availability. The current trial will evaluate a short-term structured protocol which targets a co-morbid condition often considered of primary importance by service users. If successful the intervention will be an important addition to current initiatives aimed at increasing access to psychological therapies for people diagnosed with severe mental health problems. Trial registration: Current Controlled Trials. ISRCTN99485756. Registered 13 March 2014

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Gene Ontology in 2010: extensions and refinements

The Gene Ontology (GO) Consortium (http://www.geneontology.org) (GOC) continues to develop, maintain and use a set of structured, controlled vocabularies for the annotation of genes, gene products and sequences. The GO ontologies are expanding both in content and in structure. Several new relationship types have been introduced and used, along with existing relationships, to create links between and within the GO domains. These improve the representation of biology, facilitate querying, and allow GO developers to systematically check for and correct inconsistencies within the GO. Gene product annotation using GO continues to increase both in the number of total annotations and in species coverage. GO tools, such as OBO-Edit, an ontology-editing tool, and AmiGO, the GOC ontology browser, have seen major improvements in functionality, speed and ease of use.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://nar.oxfordjournals.org/

Brief Digital Mindfulness and Compassion Training in Healthcare Professionals Drives Behavioral Change &amp; Neural Plasticity

High-stress levels have become a large part of physicians' lives in today's medical workforce, increasing only more so since the COVID-19 pandemic. Few efforts have been made to decrease these high-stress levels, leading to not only negative impacts on physicians' physical and mental well-being but also on their ability to care for patients. Prior research has shown that self-compassion and mindfulness are powerful tools in preventing burnout, but there are few resources available that incorporate these ideals effectively and are time-efficient. Through an online application, participants in our study used a digital mindfulness meditation application to train compassion and practice mindfulness. Participants also took part in an interoceptive breath monitoring task recorded pre- and post-mindfulness training. Through this breathing task, we investigated neural activity in core brain networks through electrophysiological source imaging. We discovered that mindfulness practices can increase personality attributes of self-compassion and state-mindfulness with improvements in self-compassion sustained at follow-up, overall leading to better self-management of stressors. Additionally, longer mindfulness training duration was found to be positively correlated with a greater magnitude of improvement in self-compassion across subjects. Neural results indicated plasticity specific to the default mode network (DMN) region with network suppression in the experimental group at post-intervention. Neurobehavioral correlations revealed the extent of DMN suppression related to self-compassion improvements during post- versus pre-intervention. These findings implicate that brief digital mindfulness practices may improve stress management in physicians

Brief early psychological interventions following trauma: A systematic review of the literature

A systematic literature search/review was undertaken of brief early psychological interventions following trauma. Only six randomized controlled trials were found, and none of these included group interventions. Of the six trials, two studies associated the intervention with a positive outcome, two demonstrated no difference on outcome between intervention and non-intervention groups, and two showed some negative outcomes in the intervention group. This review suggests that early optimism for brief early psychological interventions including debriefing was misplaced and that there is an urgent need for randomized controlled trials of group debriefing and other early interventions