Explore the vast range of titles available.

ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in June 2014 in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines.

A 69-year-old Chinese man presented with proptosis was found to suffer from orbital mycobacterial infection. As acid-fast bacilli were identified from orbital excisional biopsy, the patient was treated with an anti-tuberculous regimen. He responded well and was asymptomatic at 13-month follow-up. This case is documented for its rarity.

Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines.

Back injuries are the most common musculoskeletal disorder in the workplace and cost employers billions of dollars each year. Although these are widely known statistics, no comprehensive solution exists to reduce back injuries. While products like dollies and carts have been designed to solve particular tasks like moving materials, an all-encompassing solution to alleviate back injuries has yet to be proposed. This is largely due to the dynamic complexity involved with accommodating the various tasks required by different occupations. While the majority of some workers spend their days stooping to move materials, others predominantly walk bent over to perform duties like vacuuming. But at the most basic level, professions with high rates of back injuries mainly have two common motions: stooping and walking. Therefore, to successfully reduce back injuries, a device must reduce back muscle strain by supporting the torso during stooping while still permitting walking. This dissertation proposes five hip actuation designs to solve this fundamental problem. The intent is for the hip actuators to be incorporated into a full exoskeleton which interfaces with the user’s torso and legs to support the lower back during stooping and/or walking. The first hip actuation design is a simple wrap spring clutch which is beneficial for tasks like static stooping and bent walking (walking while stooped). The second hip actuation design adds a spring to the first design to conserve energy and dynamically support the back during stooping and standing upright. The third hip actuation design adds a locking feature to the spring in the second design to control when the spring’s energy is released. The fourth hip actuation design uses one large, high-torque motor to support the torso during bending and walking. The fifth hip actuation design adds a wrap spring clutch to the fourth design to reduce the complexity of the control system when a user walks. Although the proposed designs are discussed in order of increasing design complexity, the enhanced systems also accommodate additional worker tasks, making them applicable to broader audiences. Ultimately, a cost-benefit analysis weighing design complexity versus applicable tasks is necessary to determine which designs are most beneficial for production.

Food allergy is a potentially life-threatening disease which affects up to 8 % of children and 2–3 % of adults. Increasing food allergy prevalence poses a major public health concern. Induction of desensitization to food allergens through oral immunotherapy (OIT) is an expanding area of study encompassing peanut, egg, milk, and other food allergens. OIT consists of administering incremental doses of food allergen to food-allergic patients, to induce a state of desensitization. Safety, tolerability, and efficacy all remain ongoing concerns. Clinical trials for oral immunotherapy have encompassed many variations, including differences in dosage sizes and frequency, duration of build-up, type of allergen used, patient characteristics, and adjuvant therapies. Consequently, studies have also shown variation in rates of adverse effects, and successful desensitization. Here, we provide an overview of the key studies and discuss the implications of this heterogeneity. While desensitization is successful in the majority of patients, only a minority appear to develop sustained unresponsiveness even after years of therapy. Much larger and longitudinal studies using more homogenous protocols are needed in order to evaluate the clinical applicability of OIT, its long-term effectiveness, and effect on quality of life. The role of adjunctive therapies, including omalizumab and probiotics, requires further evaluation.

Dendritic cells (DC) are professional antigen presenting cells which play crucial roles in the immune system. Dendritic cells can activate and regulate immunity on many different levels: by activating naive T cells, by modulating Th1/Th2 balance, and by helping to curtail immune responses. One key to DC function is the presentation of exogenous antigen using the Major Histocompatibility Complex Class II (MHC Class II). The Class II Transactivator (CIITA) is a critical transcriptional regulator of MHC Class II and other genes involved in antigen presentation. Expression of CIITA in DC is tightly regulated and exquisitely coordinated with changes in DC physiology. The work presented in this thesis took two approaches to studying the role of CIITA in dendritic cells. First, I analyzed dendritic cells from CIITA-deficient (CIITA-/-) mice. In the absence of CIITA, dendritic cells endocytosed antigen and expressed cell surface costimulatory molecules normally. However, CIITA-/- DC produced increased amounts of IL-10, a key anti-inflammatory cytokine which modulates T cell responses and regulates the production of other cytokines. Second, I searched for new targets of regulation by CIITA by performing microarray analysis of DC from CIITA-/- mice. CIITA-/- DC expressed higher levels of cathepsin E (CatE), a protease implicated in antigen processing. CIITA repressed expression of CatE mRNA and protein and inhibited activity at CatE promoter. Decreased levels of CatE protein correlated with reduced CatE protease activity. These data show that regulation of DC by CIITA is not limited to MHC Class II and antigen presentation. By modulating cytokine production and antigen processing, CIITA can direct DC responses throughout the spectrum of their many functions.