Infectious Diseases - Research Publications
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ItemPI3K Activation in Neural Stem Cells Drives Tumorigenesis which can be Ameliorated by Targeting the cAMP Response Element Binding (CREB) Protein(Oxford University Press, 2018-10)BACKGROUND: Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions. METHODS: To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs. RESULTS: Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom-free survival in mice. CONCLUSION: Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.
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ItemHuman papillomavirus vaccination and genital warts in young Indigenous Australians: national sentinel surveillance data(Australasian Medical Publishing Company, 2017-03-20)OBJECTIVES: To examine the impact of the national human papillomavirus (HPV) vaccination program (available to girls and women [12-26 years] since 2007 and to boys [12-15 years] since 2013) on the number of diagnoses of genital warts in Australian Aboriginal and Torres Strait Islander (Indigenous) people. DESIGN, SETTING, PARTICIPANTS: Analysis of routinely collected data from patients attending 39 sexual health clinics (SHCs) in the Genital Warts Surveillance Network for the first time.Major outcome: The average annual proportion of Indigenous and non-Indigenous SHC patients diagnosed with genital warts during the pre-vaccination (2004-2007) and vaccination periods (2008-2014), stratified by age group and sex. RESULTS: 7.3% of the 215 599 Australian-born patients with known Indigenous status and seen for the first time at participating SHCs during 2004-2014 were Indigenous Australians. The average proportion of female Indigenous patients diagnosed with warts was lower during the vaccination period than during the pre-vaccination period (in those under 21, summary rate ratio [SRR], 0.12; 95% CI, 0.07-0.21; P < 0.001); in 21-30-year olds: SRR, 0.41; 95% CI, 0.27-0.61; P < 0.001); there was no significant difference for women over 30 (SRR, 0.84; 95% CI, 0.51-1.36; P = 0.47). The proportion of male Indigenous heterosexual SHC patients under 21 diagnosed with warts was also lower during the vaccination period (SRR, 0.25; 95% CI, 0.12-0.49; P < 0.001), with no significant changes among older Indigenous men over 30. CONCLUSIONS: There were marked declines in the proportions of diagnoses of genital warts in young Indigenous women and men attending SHCs after the introduction of the HPV vaccination program. If high levels of HPV vaccine coverage are sustained, HPV-related cancer rates should also decline.
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ItemPrevalence of HIV among Aboriginal and Torres Strait Islander Australians: a systematic review and meta-analysis(Commonwealth Scientific and Industrial Research Organization Publishing, 2017)Background: Aboriginal and Torres Strait Islanders (Aboriginal) are Australia’s first peoples. Between 2006 and 2015, HIV notifications increased among Aboriginal people; however, among non-Aboriginal people, notifications remained relatively stable. This systematic review and meta-analysis aims to examine the prevalence of HIV among Aboriginal people overall and by subgroups. Methods: In November 2015, a search of PubMed and Web of Science, grey literature and abstracts from conferences was conducted. A study was included if it reported the number of Aboriginal people tested and those who tested positive for HIV. The following variables were extracted: gender; Aboriginal status; population group (men who have sex with men, people who inject drugs, adults, youth in detention and pregnant females) and geographical location. An assessment of between study heterogeneity (I2 test) and within study bias (selection, measurement and sample size) was also conducted. Results: Seven studies were included; all were cross-sectional study designs. The overall sample size was 3772 and the prevalence of HIV was 0.1% (I2 = 38.3%, P = 0.136). Five studies included convenient samples of people attending Australian Needle and Syringe Program Centres, clinics, hospitals and a youth detention centre, increasing the potential of selection bias. Four studies had a sample size, thus decreasing the ability to report pooled estimates. Conclusions: The prevalence of HIV among Aboriginal people in Australia is low. Community-based programs that include both prevention messages for those at risk of infection and culturally appropriate clinical management and support for Aboriginal people living with HIV are needed to prevent HIV increasing among Aboriginal people.
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ItemTrends in hepatitis C antibody prevalence among Aboriginal and Torres Strait Islander people attending Australian Needle and Syringe Programs, 1996-2015(ELSEVIER, 2017-09)BACKGROUND: Research indicates that hepatitis C antibody (anti-HCV) prevalence is higher among Australian Aboriginal and Torres Strait Islander (Aboriginal) than non-Aboriginal people who inject drugs (PWID). We examined trends in demographic and drug use characteristics and anti-HCV prevalence among Australian Needle and Syringe Program Survey (ANSPS) respondents by Aboriginal status from 1996 to 2015. METHODS: The ANSPS survey involved collecting demographic, behavioural data and a dried blood spot for anti-HCV testing. We used logistic regression to determine demographic and behavioural factors associated with testing anti-HCV positive in the following time-periods (1996-2000, 2001-2005, 2006-2010, 2011-2015) among Aboriginal and non-Aboriginal PWID respondents. RESULTS: Overall, there were 16,948 PWID, with 11% identifying as Aboriginal. The proportion of Aboriginal respondents increased from 7% in 1996-2000 to 16% in 2011-2015. Overall anti-HCV prevalence was significantly higher among Aboriginal (60%) than non-Aboriginal PWID (52%, p<0.01). Receptive syringe sharing (RSS) declined among non-Aboriginal PWID (p<0.001) over time, however among Aboriginal PWID, RSS remained stable (p=0.619). Factors independently associated with testing positive for anti-HCV among Aboriginal PWID in 2011-2015 were 16 or more years since first injection (adjusted odds ratio [AOR] 6.04, p<0.001), history of incarceration (AOR: 1.74, p=0.010) and currently or previously on opioid substitution therapy (AOR: 1.89, p=0.003). Compared to 1996-2000, testing anti-HCV positive was significantly associated with the time-periods: 2001-2005 (unadjusted odds ratio [OR]: 1.39, p<0.001), 2006-2010 (OR: 1.38, p<0.001) and 2011-2015 (OR: 1.25, p<0.001) among non-Aboriginal PWID; however this increase did not occur among Aboriginal PWID. CONCLUSION: The proportion of Aboriginal PWID attending Needle Syringe Programs appears to have increased. Overall, the prevalence of anti-HCV has remained higher among Aboriginal than non-Aboriginal PWID. Coupling increased access to NSPs with new interferon-free HCV treatments and culturally appropriate education and counselling services could influence new HCV infections among Aboriginal PWID.
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ItemSexually Transmitted Infections Among Young Men Who Have Sex with Men: Experiences with Diagnosis, Treatment, and Reinfection(SPRINGER, 2018-06)Despite high rates of sexually transmitted infections (STIs) among young men who have sex with men (YMSM), little is known about their experiences with diagnosis, treatment, and reinfection. To fill this gap, we interviewed 17 YMSM ages 18-29 who participated in an online HIV prevention trial and tested positive for STIs at both the baseline and three-month follow-up assessments. Participants were asked about their reactions to testing positive, experiences with treatment, disclosure to partners, and changes in thinking and behavior. Reactions were diverse, the most common being surprise and concern. Most participants sought treatment, although type of provider varied (e.g., primary care physician, clinic that specialized in gay/bisexual men's health). Providers tended to re-test participants, but some did so at the incorrect anatomical site. Participants who felt comfortable talking to providers about STIs tended to use their regular provider or one who specialized in gay/bisexual men's health. Most participants described changes in their thinking and behavior (e.g., increased condom use, decreased sex partners, questioning their partners' trust). Most participants disclosed to at least one partner, but some did not remember or were not in contact with partners. Experiences were similar the first and second time participants tested positive for STIs during the study with a few exceptions (e.g., more self-blame and comfort talking to providers the second time). In sum, YMSM have diverse experiences with STI diagnosis and treatment. Implications for public policy and STI prevention are discussed.
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ItemEpigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice.(Springer Science and Business Media LLC, 2018-02-02)Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.
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ItemOvarian abscess caused by Salmonella enterica serovar Typhi: a case report.(Springer Science and Business Media LLC, 2019-09-25)BACKGROUND: Typhoid fever is a human-specific disease caused by a bacterium, Salmonella enterica subspecies enterica serovar Typhi. It is transmitted through ingestion of contaminated food or water. It is mostly diagnosed by blood culture. Salmonella Typhi usually manifests as a febrile illness with bacteremia after initial entry through the gastrointestinal route, but it can occasionally cause significant disease in extraintestinal sites. We report a case of a girl in Fiji with a right ovarian abscess infected by Salmonella Typhi. CASE PRESENTATION: A 14-year-old iTaukei (indigenous Fijian) girl presented to our hospital with abdominal pain of 1 month's duration. Two days prior to her admission, she developed high-grade fever and nausea and had one episode of vomiting. On presentation, she appeared unwell; she was tachycardic (116 beats per minute) and febrile (38.8 °C). Her abdominal examination revealed generalized tenderness. Other examination findings were normal. The provisional diagnosis of abdominal sepsis led to an emergency laparotomy during which an enlarged right ovary was found to be spontaneously discharging pus. The ovary was incised and drained, and the patient was commenced on intravenous ceftriaxone 1 g twice daily, cloxacillin 1 g four times daily, and metronidazole 500 mg three times daily. She recovered promptly and was discharged to home on the sixth postoperative day. The purulent material from the ovary grew Salmonella Typhi. CONCLUSION: Extraintestinal infections caused by Salmonella Typhi are rare but can cause severe and life-threatening disease. Our patient had a prolonged history of abdominal pain and was found to have a ruptured right ovarian abscess due to Salmonella Typhi. Ovarian abscesses in girls who are not sexually active are not associated with pelvic inflammatory disease and suggest local or hematogenous spread. This case report may increase health workers awareness to include common and endemic infections in the differential diagnosis of unusual clinical presentations to help the initiation of appropriate investigation and management as quickly as possible.
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ItemDengue in Fiji: epidemiology of the 2014 DENV-3 outbreak.(World Health Organization, Western Pacific Regional Office, 2019)INTRODUCTION: Dengue virus serotype-3 caused a large community-level outbreak in Fiji in 2013 and 2014. We aimed to characterize the demographic features of affected individuals and to determine dengue mortality during the outbreak. METHODS: All laboratory-confirmed dengue cases and deaths were included in this study. Incidence and mortality were calculated according to demographic variables. RESULTS: A total of 5221 laboratory-confirmed cases of dengue were included in this analysis. The majority of patients were male (54.5%) and indigenous Fijians (iTaukei) (53.5%). The median age was 25 years old. The overall incidence was 603 per 100 000 population. The age-specific incidence was highest among people between 20 and 24 years of age (1057 per 100 000) for both sexes. The major urban and peri-urban areas of Suva and Rewa subdivisions reported the highest incidence of > 1000 cases per 100 000 population.: A total of 48 deaths were included in this analysis. The majority of dengue-related deaths occurred in males (62.5%) and in the iTaukei (60.4%) population. The median age at death was 35 years old. The overall dengue-related deaths was estimated to be 5.5 deaths per 100 000 population. Dengue mortality was higher for males (6.8 per 100 000) than females. The highest age- and sex-specific mortality of 18 per 100 000 population was among males aged 65 years and older. DISCUSSION: Dengue morbidity and mortality were highest among males, indigenous people and residents of urban and peri-urban locations. Effective and integrated public health strategies are needed to ensure early detection and appropriate outbreak control measures.
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ItemImmunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial(ELSEVIER SCI LTD, 2019-05)BACKGROUND: Few data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13. METHODS: In this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510. FINDINGS: Of 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10-PCV13 risk difference -2·1% [95% CI -4·8 to -0·1] for serotype 1; -1·3% [-3·7 to 0·6] for serotype 4; -3·4% [-6·8 to -0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; -1·3% [-3·7 to 0·6] for serotype 7F; -1·6% [-5·1 to 1·7] for serotype 9V; 0·0% [-2·7 to 2·9] for serotype 14; -2·1% [-5·3 to 0·9] for serotype 18C; 0·0% [-2·2 to 2·3] for serotype 19F; and -11·6% [-18·2 to -4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups. INTERPRETATION: PCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings. FUNDING: National Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.