Background Avian influenza A (H5N1) has been circulating around and remains to be one of the major threats to human beings since it first emerged in 1997. Besides vaccines, currently there are two major countermeasures to infection in clinical settings, which are antiviral therapies and immunomodulator treatments. Objectives To summarize evidence on the effectiveness of current treatments against H5N1 infection and to explore the potential benefits of several immunomodulatory agents. Design Systematic review of cross-sectional studies and case series. Data sources Searches of PubMed for articles using the search term “(H5N1[Title]) AND antiviral[Title/Abstract]” and also manual search on PubMed for studies that are cited in some review papers in the first automatic search. Previous search results relating to human H5N1 infection studies are also included. Study selection Included studies that were human H5N1 infection cross-sectional studies or case series in which clinical outcomes were reported, CFR and survival rate were specified or could be easily derived from original data. Results 11 articles met the selection criteria and were included in our analysis. Sample size of the included studies ranged from 8 to 308 lab confirmed cases with median age varied from 10 to 29. Leukopenia, lymphopenia, thrombocytopenia and elevated ALT and AST at admission were strongly associated with worse clinical outcomes with different significance across studies. Oseltmivir treatment was generally initiated earlier among those who survived. Survival benefit of oseltamivir was the most significant if the patient received the treatment within the first two days after symptom onset, and it is still significantly effective when treatment was given up to eight days after symptom onset according to one study we included. Corticosteroid didnot show any beneficial effect or it is associated with a higher risk of death when it is given according to the current treatment protocol and a delayed initiation time. Conclusion Oseltamivir treatment is associated with survival benefit especially when initiated within the first two days after symptom onset, while immunomodulator therapies haven’t shown such benefit so far in clinical setting but some experiments in vitro and in vivo support their use in a manner which is different from the current protocol. / published_or_final_version / Public Health / Master / Master of Public Health

Introduction: The market for chronic disease management apps for patients is growing from year to year. However, policy and regulation of app use for medical purposes in Asia Pacific are not developed. Methods: 1) A systematic review of randomized-controlled trials of diabetes management apps for patients are assessed as to determine whether using the app (intervention group) leads to significant reductions in HbA1c levels ; 2) A comparison of paid and free apps based on number of group functions between Apple iTunes App Store and Google Play for Android. Results: 1) A reduction in HbA1c in both the intervention (m-Health) and control (usual care) group, although two studies identified the changes as statistically insignificant; 2) Apple iTunes App store included 95 free diabetes management apps for patients and 86 paid apps at an average cost of $19.91. Google Play offered 80 free apps and 31 paid apps at an average cost of $4.31. The largest HbA1c reductions could be found when clinical, social, behavioural, and affective factors are taken into account in the app’s supporting system (e.g. WellDoc™ System (WDS). Discussion: There is some evidence to suggest that mobile apps for diabetes management for patients show reductions in HbA1c similar to usual care. In Hong Kong, some progress has been made regarding the promotion of the use of m-Health for the elderly and disabled, but policies on app development, approval, and regulation are absent. Future expansion of ICT may consider m-Health for chronic disease management based on international lessons on medical device and medical apps guidelines. / published_or_final_version / Public Health / Master / Master of Public Health

Background Traditional medication therapy and psychotherapy are commonly used for treatment drug abstinence syndrome. Because of the side effects of traditional medication therapy (MT), acupuncture therapy (AT) is under investigation for treating abstinence syndrome, particularly for heroin detoxification. This project aims to review different randomised clinical trials (RCTs) of heroin detoxification treatment by acupuncture, and retrieve relevant data so that appropriate suggestions can be made to the Narcotics Division (ND), the Department of Health (DH), non-governmental organisations (NGOs) and related local public health institutes for the anti-drug services of heroin and opioid drugs. Methods A systematic review was conducted using PubMed and Google Scholar to retrieve 13 relevant articles of randomised clinical trials (RCTs) in English and Chinese conducted from 2000 to 2014. These RCTs contained data of heroin-dependent patients, details of assessment of abstinence syndrome and treatments; and comparison of efficacy of AT with MT, such as side effects, severity and relapse of heroin abstinence in physical and psychological aspects. Results 13 articles were included. All treatments were conducted in clinics or hospitals. Different intervention strategies were included, comparing AT with MT, AT plus MT with MT alone, AT with no treatment as well as true AT with superficial AT. All trials have reported better therapeutic effects in the heroin abusers with AT, regardless the use of medication, age and sex. Improved treatment effects were demonstrated in reducing psychological effect of heroin abstinence, such as anxiety and depression, sleep quality, relapse and heroin craving. Also, improved treatment of physical effects of abstinence was shown by increasing body weight, improved liver and kidney functions, improved immunity and lower adverse effects than conventional MT. No adverse effect was reported in 3 trials (23%) or mentioned in 9 trials (69%), mild adverse effects was reported in 1 trial. Conclusions ND, DH, NGOs and other local public health institutes should conduct further studies in Hong Kong to obtain primary local data of the therapeutical effects of AT, and implement AT as an adjunct to the traditional MT and psychotherapy for treating heroin abstinence syndrome due to it high efficacy, safety and low side effects. / published_or_final_version / Public Health / Master / Master of Public Health

Lupus nephritis (LN)is an important clinical manifestation of systemic lupus erythematosus (SLE)and contributes significantly to patient morbidity and mortality. In the era of effective immunosuppressive treatments, the clinical outcomes of LN patients have substantially improved, and the10-year patient and renal survival rates were98.2% and 98.0% respectively. With prolonged patient survival, infection (50.0%), cardiovascular disease (20.8%) and malignancy(12.5%)but not uncontrolled disease, have emerged as the leading causes of death in LN patients. The strongest predictor of mortalityin LN patients, however, was endstage renal disease (ESRD)as indicated by a high standardized mortality ratio of 26.1which doubled that of cardiovascular disease and history of malignancy. Despite the improved patient outcomes, conventional treatment such as cyclosphosphamide (CTX) was associated with significant toxicities and suboptimal long-term renal prognosis and hence alternative immunosuppressive agents with anti-fibrotic properties such as mycophenolate mofetil (MMF) and proliferation signal inhibitors (PSI)warrants further investigation. In Chinese patients with proliferative LN, corticosteroids and MMF as initial therapy conferred favorable long-term outcomes, with 10-year patient and renal survival of91% and 86% respectively. This regimen, when used as continuous induction-maintenance treatment, is Efficacious and well-tolerated, and the continuation of MMF treatment for at least 24 months was associated with significantly lower risk of relapse when compared to treatment for shorter duration. As the severity of tubulointerstitial fibrosis can be attenuated by growth factors with anti-fibrotic properties such as bone morphogenetic protein 7 (BMP7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), studies were conducted in NZB/W F1 mice to investigate the impact of treatment on intra-renal expression of growth factors pertinent to fibrosis. Methylprednisolone (MP) combined with either MMF or CTX have resulted in increased BMP7 and reduced HGF and VEGF in the renal parenchyma, reduced fibrosis, and improved clinical parameters, compared with MP alone. The data also suggested that the increase in BMP7, a potentially anti-fibrotic cytokine, was observed earlier in the mice treated with MMF compared with those treated with CTX. Our preliminary clinical experience also suggested that PSI combined with corticosteroids may serve as an efficacious and well-tolerated immunosuppressive regimen in human LN, especially in patients with MMF intolerance or history of malignancy. These observations have important implications on the choice of therapy for the treatment of proliferative LN. As for membranous LN, our pilot results suggested that corticosteroids combined with either MMF or tacrolimus can be effective treatment options for patients with significant proteinuria, while each regimen exhibits distinct efficacy and tolerability profiles. In conclusion, the results from the studies included in this thesis show the magnitude of benefit conferred by novel immunosuppressive treatment regimens for LN on renal and patient survival, and on the associated intra-renal mechanisms pertaining to fibrosis. / published_or_final_version / Medicine / Master / Doctor of Medicine

abstract / Anatomy / Doctoral / Doctor of Philosophy

Major depressive disorder (MDD) is a prevalent and disabling disorder worldwide and in Hong Kong. It can occur alone or as a psychiatric sequelae of stroke known as post stroke depression (PSD). Our recent randomized controlled trial (RCT) found that additional dense cranial electroacupuncture stimulation (DCEAS) produced significantly greater improvement on depressive symptoms in patients with MDD compared to conventional antidepressants alone. However, the effectiveness of DCEAS on PSD and the underlying neural mechanism of its antidepressant effects remain unclear and need further investigation. This thesis consisted of three studies aimed to evaluate the efficacy of DCEAS as an additional therapy in PSD and to explore the neuroimaging correlates of DCEAS in MDD using PET and fMRI modalities. The purpose of Study 1 was to examine whether additional DCEAS was effective in treating PSD. A single blind RCT was conducted in 43 PSD patients treated with antidepressants and same body acupuncture combined with sham or active DCEAS with 3 acupuncture sessions per week for 4 weeks. Clinical outcomes included the Hamilton Depression Rating Scale 17-Item (HAMD-17), Clinical Global Impression - Severity Scale (CGI-S), and Barthel Index (BI).The results showed that DCEAS significantly reduced HAMD-17 at week 1, CGI-S at week 1 and endpoint whereas BI was more significantly decreased in control group. A combination of DCEAS and body acupuncture can be considered as an augmenting treatment for PSD. Study 2 aimed to explore the potential effects of DCEAS in regulating abnormal glucose metabolism in patients with MDD using 18F-FDG PET/CT. A single blind RCT was conducted in 25 MDD patients treated with antidepressants combined with sham or active DCEAS with 3 acupuncture sessions per week for 6 weeks. Clinical outcomes were measured using the HAMD-17, Zung Self-Rating Depression Scale (SDS), CGI-S and Insomnia Severity Index (ISI). There was a significant difference on the slope in SDS in linear mixed model analysis, indicating a faster improvement in subjective depressive symptoms by DCEAS. While the increased 18F-FDG signals in the cerebellum were normalized in both groups, the reversion of the reduced 18F-FDG signals in the left prefrontal cortex was only observed in DCEAS-treated patients, suggesting that additional DCEAS could more vigorously improve abnormal brain glucose metabolism in MDD. The purpose of Study 3 was to further investigate the neuropsychological and functional neuroimaging correlates of the antidepressant effects of DCEAS in the same pool of MDD subjects in Study 2 using fMRI with sad-face paradigm. The sad-face stimulation increased BOLD signals in an extensive neural network of the brain, including the frontal, temporal, parietal, limbic system and cerebellum. Additional DCEAS extensively suppressed the abnormal BOLD signals in these brain regions, more apparently in left caudate and cingulate, whereas sham treatment had slightly suppressive effects in fewer brain regions, suggesting that additional DCEAS could more robustly alter the biases towards sadness in MDD. In conclusion, DCEAS additional treatment is more effective in reducing depressive symptoms in patients with PSD, improving brain glucose metabolism and normalizing the abnormal neural activation due to biases towards sadness in patients with MDD. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

In the present study, the anti-tumor efficacy of α-TEA, a derivative of RRR-α-tocopherol, was investigated in LNCaP and PC-3-GFP human prostate cancer cells. Data show that α-TEA induced apoptosis in both cell lines in a time- and dose-dependent manner. Data show that α-TEA induces apoptosis through the activation of pro-apoptotic Fas signaling and inhibition of pro-survival Akt signaling pathways. The role of FADD and Daxx in α-TEA-induced apoptosis was determined. Data show that α-TEA promotes the association of FADD with Fas. FADD siRNA significantly reduced α-TEA-induced apoptosis in LNCaP cells. However, in PC-3-GFP cells, FADD siRNA caused apoptosis in the absence of α-TEA, and in the presence of FADD siRNA, α-TEA-induced apoptosis was significantly enhanced, indicating pro-survival activity of FADD in PC-3-GFP cells. Although α-TEA did not change the total protein levels of Daxx, it did promote the association of Daxx with Fas. α-TEA-induced apoptosis was significantly reduced by Daxx siRNA, and enhanced by overexpression of wild type Daxx, showing the pro-apoptotic role of Daxx in α-TEA-induced apoptosis. α-TEA inhibited phosphorylation of all three Akt isoforms; namely, Akt1, Akt2, and Akt3, thereby removed the phosphorylation inhibition on FOXO1 and FOXO1-mediated upregulation of FasL enhanced apoptosis through Fas signaling pathway. Studies have shown that selenium is of value in prostate cancer prevention. Here we document that methylseleninic acid (MSA) acts synergistically with α-TEA to induce apoptosis in LNCaP and PC-3-GFP human prostate cancer celld in culture. Western blot analyses indicate the involvement of caspases-8, -9, and -3, as well as Akt, in the synergistic effect of α-TEA and MSA. In a preclinical PC-3-GFP xenograft mouse model, α-TEA and MSC separately and together significantly reduced tumor burden and metastatic lesions in lungs and lymph nodes. However, synergism with the combination that in cell culture were not obtained in the animal study. α-TEA alone was as effective as, perhaps better than, the combination treatment in ruducing tumor burden and inhibiting metastases. Thus, data support α-TEA alone, rather than α-TEA plus selenium, as a treatment for human prostate cancer. / text

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