SARS-CoV-2 nucleocapsid protein, rather than spike protein, triggers a cytokine storm originating from lung epithelial cells in patients with COVID-19.

PURPOSE: The aim of this study was to elucidate the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may initiate cytokine cascades and correlate the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with their serum cytokine profiles. METHODS: Recombinant baculoviruses displaying SARS-CoV-2 spike or nucleocapsid protein were constructed and transfected into A549 cells and THP-1-derived macrophages, to determine which protein initiate cytokine release. SARS-CoV-2-specific antibody titers and cytokine profiles of patients with COVID-19 were determined, and the results were associated with their clinical characteristics, such as development of pneumonia or length of hospital stay. RESULTS: The SARS-CoV-2 nucleocapsid protein, rather than the spike protein, triggers lung epithelial A549 cells to express IP-10, RANTES, IL-16, MIP-1α, basic FGF, eotaxin, IL-15, PDGF-BB, TRAIL, VEGF-A, and IL-5. Additionally, serum CTACK, basic FGF, GRO-α, IL-1α, IL-1RA, IL-2Rα, IL-9, IL-15, IL-16, IL-18, IP-10, M-CSF, MIF, MIG, RANTES, SCGF-ß, SDF-1α, TNF-α, TNF-ß, VEGF, PDGF-BB, TRAIL, ß-NGF, eotaxin, GM-CSF, IFN-α2, INF-γ, and MCP-1 levels were considerably increased in patients with COVID-19. Among them, patients with pneumonia had higher serum IP-10 and M-CSF levels than patients without. Patients requiring less than 3 weeks to show negative COVID-19 tests after contracting COVID-19 had higher serum IP-10 levels than the remaining patients. CONCLUSION: Our study revealed that nucleocapsid protein, lung epithelial cells, and IP-10 may be potential targets for the development of new strategies to prevent, or control, severe COVID-19.

Association of protein disulfide isomerase family A, member 4, and inflammation in people living with HIV.

OBJECTIVES: Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins associated with inflammation, obesity, and cancer. In HIV infection, the role of PDI family A, member 4 (PDIA4), is unclear. This study aimed to clarify the association between plasma PDIA4 levels and inflammation in people living with HIV (PLWH). METHODS: In this study, 287 PLWH and 74 healthy participants were enrolled. The plasma PDIA4 values, demographic data, laboratory data, and other inflammatory markers were recorded. The association between PDIA4 level and inflammatory extent was analyzed using logistic regression and Spearman rank-order correlations. Other results were analyzed using Student's t-test or chi-square test. RESULTS: In PLWH, the PDIA4 levels were positively associated with the inflammatory markers, interleukin 6 (r = 0.209, p = 0.001), and tumor necrosis factor-α (r = 0.162, p = 0.01) levels, but not with high-sensitivity C-reactive protein levels. Moreover, the plasma PDIA4 level of PLWH decreased after anti-viral treatment (p = 0.0001). CONCLUSION: Plasma PDIA4 levels are closely associated with inflammation in PLWH and have a positive correlation with the viral load during anti-viral therapy.

Clinical Characteristics of COVID-19 Patients and Application to an Artificial Intelligence System for Disease Surveillance.

During the coronavirus disease (COVID-19) pandemic, we admitted suspected or confirmed COVID-19 patients to our isolation wards between 2 March 2020 and 4 May 2020, following a well-designed and efficient assessment protocol. We included 217 patients suspected of COVID-19, of which 27 had confirmed COVID-19. The clinical characteristics of these patients were used to train artificial intelligence (AI) models such as support vector machine (SVM), decision tree, random forest, and artificial neural network for diagnosing COVID-19. When analyzing the performance of the models, SVM showed the highest sensitivity (SVM vs. decision tree vs. random forest vs. artificial neural network: 100% vs. 42.86% vs. 28.57% vs. 71.43%), while decision tree and random forest had the highest specificity (SVM vs. decision tree vs. random forest vs. artificial neural network: 88.37% vs. 100% vs. 100% vs. 94.74%) in the diagnosis of COVID-19. With the aid of AI models, physicians may identify COVID-19 patients earlier, even with few baseline data available, and segregate infected patients earlier to avoid hospital cluster infections and to ensure the safety of medical professionals and ordinary patients in the hospital.

Immune Reconstitution Inflammatory Syndrome Induced by Mycobacterium avium Complex Infection Presenting as Chronic Inflammatory Demyelinating Polyneuropathy in a Young AIDS Patient.

Antiretroviral therapy (ART) can restore protective immune responses against opportunistic infections (OIs) and reduce mortality in patients with human immunodeficiency virus (HIV) infections. Some patients treated with ART may develop immune reconstitution inflammatory syndrome (IRIS). Mycobacterium avium complex (MAC)-related IRIS most commonly presents as lymphadenitis, soft-tissue abscesses, and deteriorating lung infiltrates. However, neurological presentations of IRIS induced by MAC have been rarely described. We report the case of a 31-year-old man with an HIV infection. He developed productive cough and chronic inflammatory demyelinating polyneuropathy (CIDP) three months after the initiation of ART. He experienced an excellent virological and immunological response. Sputum culture grew MAC. The patient was diagnosed with MAC-related IRIS presenting as CIDP, based on his history and laboratory, radiologic, and electrophysiological findings. Results: Neurological symptoms improved after plasmapheresis and intravenous immunoglobulin (IVIG) treatment. To our knowledge, this is the first reported case of CIDP due to MAC-related IRIS. Clinicians should consider MAC-related IRIS in the differential diagnosis of CIDP in patients with HIV infections following the initiation of ART.

Growth arrest-specific 6 protein in HIV-infected patients: Determination of plasma level and different antiretroviral regimens.

BACKGROUND/PURPOSE: Growth arrest-specific 6 (Gas6) protein is involved in cell proliferation, differentiation, adhesion, migration in response to inflammatory processes. Human immunodeficiency virus (HIV) infection induces a chronic inflammatory condition and combination of antiretroviral therapy improves immune function and decreases the inflammatory state. The aim of this study was to assess the implications of Gas6 in chronic inflammation status of HIV-infected patients undergoing different third regimens of antiretroviral therapy. The Gas6 may be a marker of chronic inflammation of HIV-infected patients. METHODS: A total of 356 adult males, including 258 HIV-infected patients and 98 healthy controls, were recruited. The demographic and clinical characteristics of the patients were collected. Laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), hepatitis B and C viruses, and serum biochemistry. Plasma Gas6 concentrations were determined. RESULTS: The values of Gas6 were lower in HIV patients compared to healthy subjects (14.3 ± 6.4 vs 21.5 ± 15.2, p = 0.01). HIV patients that received antiviral regimen with abacavir had similar Gas6 level than those who received antiviral regimens with tenofovir (14.3 ± 6.5 vs 13.8 ± 5.9, p = 0.99). HIV patients that received antiviral regimen with protease inhibitors (PIs) had lower Gas6 level (13.1 ± 3.5 vs 14.2 ± 6.6 vs 14.6 ± 6.5, p = 0.03) than those who received antiviral regimens with non-nucleoside reverse transcriptase inhibitors (nNRTIs) and integrase inhibitors (INSTIs), respectively. CONCLUSIONS: Decreased plasma Gas6 concentrations were observed in HIV patients. Gas6 levels are associated with different third regimen of highly active antiretroviral therapy. Gas6 may represent a unique marker for assessing the chronic inflammation state difference among cART regimens in HIV patients.

Micafungin Inhibits Dengue Virus Infection through the Disruption of Virus Binding, Entry, and Stability.

Dengue fever is an arbovirus disease caused by infection with the dengue virus (DENV). Half of the world's population lives under the threat of dengue fever, however, researchers have yet to develop any drugs that are clinically applicable to this infection. Micafungin is a member of the echinocandins family of anti-fungal drugs, capable of blocking the synthesis of ß-1,3-D-glucan in the walls of fungal cells. Previous studies have demonstrated the effectiveness of Micafungin against infections of enterovirus 71 (EV71) and chikungunya virus (CHIKV). This is the first study demonstrating the effectiveness of micafungin in inhibiting the cytopathic effects of dengue virus serotype 2 (DENV-2) in a dose-dependent manner. Time-of-addition assays verified the inhibitory effects of micafungin in pre-treated, co-treated, and full-treatment groups. Binding and entry assays also demonstrated the effectiveness of micafungin in the early stage of DENV-2 infection. The virucidal efficacy of micafungin appears to lie in its ability to destroy the virion. Molecular docking assays revealed the binding of micafungin to the envelope protein of DENV-2, thereby revealing the mechanism by which micafungin affects the early stage of DENV infection and the stability of DENV. Two other micafungin analogs, caspofungin and anidulafungin, were also shown to have the antiviral effects on DENV-2. Finally, immunofluorescence assay (IFA) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) confirmed the broad anti-DENV ability of micafungin against dengue virus serotypes 1, 3, and 4 (DENV-1, DENV-3, and DENV-4). Taken together, these results demonstrate the potential of micafungin and its analogs as candidates for the development of broad-spectrum treatments for DENV infection.

Positive Anti-SSA/Ro Antibody in a Woman with SARS-CoV-2 Infection Using Immunophenotyping: A Case Report.

The clinical spectrum of novel coronavirus infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia, with respiratory failure and even death. Autoantibodies, especially antiphospholipid antibodies, can occur in severe infections. Other autoantibodies are seldom reported. Here, a 60-year-old female patient without dry-mouth symptoms detected positive for anti-60 kDa SSA/Ro antibodies on day 43 after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To investigate this unique clinical case of SARS-CoV-2 infection, immunological characteristics of this case were detected by using flow cytometry and were compared to the other three groups of patients-health subjects, 2019 novel coronavirus disease (COVID-19) recovery patients, and Sjögren's syndrome (SS) patients. Monitoring the autoantibody level and the development of subsequently related autoimmune diseases are warranted after SARS-CoV-2 infection.

Demographic differences in people living with HIV according to recruitment sources: comparison between health-care systems and social media networks.

With the improvement of internet technology in health applications, the utilization of internet and social media as new survey methodologies and recruitment source for research participants have been encouraged, yet evidence of the feasibility in people living with HIV (PLHIV) study is still lacking. We conducted a cross-sectional survey to determine whether there are differences among PLHIV recruited from social media networks and health-care systems using an HIV stigma and discrimination questionnaire. The result revealed that PLHIV recruited from social media networks were younger, more sexually active, and had higher educational status and awareness of the country's HIV rights protection laws than those recruited from hospitals. By contrast, participants recruited from hospitals were more diverse regarding key population compositions, had lived with HIV for a longer duration, had a higher prevalence of concomitant physical disabilities than those recruited from social media networks, and fit Taiwan PLHIV characteristics described by 2016 census from Taiwan Centres for Disease Control. We conclude that sampling bias exists when utilizing social media networks for PLHIV studies.

Anti-inflammatory and anti-osteoarthritis effects of Cm-02 and Ck-02.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

Risk of Parkinson disease in Sjögren syndrome administered ineffective immunosuppressant therapies: A nationwide population-based study.

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.

Early Seroreversion After 2 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus-Positive Patients: Incidence and Associated Factors.

Serological responses (Seroresponse) and durability of hepatitis A virus (HAV) vaccination are reduced among human immunodeficiency virus (HIV)-positive patients. Incidence of and associated factors with early seroreversion (loss of seroresponse) among HIV-positive patients who have achieved seroresponses after two doses of HAV vaccination remain unclear. In this multicenter study, we followed HIV-positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A between 2015 and 2017, a 1:4 case-control study was conducted to identify factors associated with seroreversion. Case patients were those with seroreversion, and controls were those with similar follow-up durations who were able to maintain seroresponses. During the study period, 49 of the 1,256 patients (3.9%) seroreverted after a median follow-up of 611 days. In a case-control study, seroreversion was more likely to occur in patients with a higher weight (adjusted odds ratio [aOR], 1.703; 95% confidence interval [CI], 1.292-2.323, per 10-kg increment) and HIV viremia at the time of vaccination (aOR, 2.922; 95% CI, 1.067-7.924), whereas positive seroresponse at 6 months of HAV vaccination and higher CD4 lymphocyte counts at vaccination were inversely associated with early seroreversion with an aOR of 0.059 (95% CI, 0.020-0.154) and 0.837 (95% CI, 0.704-0.979, per 100-cell/mm3 increment), respectively, in multivariable analyses. Conclusion: During an outbreak setting, early seroreversion following two-dose HAV vaccination occurred in 3.9% of HIV-positive patients. Lower and delayed seroresponses to HAV vaccination, a higher weight, and HIV viremia and lower CD4 lymphocyte counts at the time of HAV vaccination were associated with early seroreversion. Regular monitoring of seroresponse and booster vaccination might be warranted, especially in HIV-positive adults with predictors of early seroreversion.

Clinical features of acute human immunodeficiency virus infection in Taiwan: A multicenter study.

BACKGROUND/PURPOSE: Acute HIV infection is characterized by a high concentration of HIV RNA in the plasma and rapid depletion of the CD4 cell count. This multicenter, retrospective observational study aimed to characterize the manifestations of acuteHIV infection in Taiwan. METHODS: Between 1 January 2012 and 31 December 2016, all patients aged 20 years or greater who presented with acute HIV infection were included. Demographic and clinical characteristics of the patients at diagnosis were collected. Baseline laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), serologic markers of syphilis and hepatitis A, B, and C viruses, and serum biochemistry. RESULTS: The proportion of acute HIV infection was 6.9% among the patients with newly diagnosed HIV infection during the study period. The most common presenting symptoms of acute HIV infection were fever, fatigue, and myalgia. The median PVL at diagnosis was 5.9 log10 copies/ml, and median CD4 count was 307 cells/mm3. A total of 68 patients (27%) had baseline CD4 count less than 200 cells/mm3. Multiple logistic regression analysis, showed that the baseline CD4 count (OR, 4.02; p = 0.013) and aspartate aminotransaminase levels (OR, 3.49; p = 0.002) were associated with high PVL (>5 log10 copies/ml); and high baseline PVL (OR, 2.64; p = 0.002) was associated with symptomatic acute HIV infection. CONCLUSIONS: Manifestations of acute HIV infection are nonspecific and of wide spectrum ranging from fever to severe illness. A higher proportion of patients with initial CD4 counts of 200 cells/mm3 or less during acute HIV infection warrants early, timely diagnosis and treatment to prevent rapid disease progression.

Monitoring early developed low bone mineral density in HIV-infected patients by intact parathyroid hormone and circulating fibroblast growth factor 23.

BACKGROUND/PURPOSE: HIV-infected patients have a high prevalence of low bone mineral density (BMD), but BMD changes remain unclear. This cross-sectional retrospective observational study aimed to characterize the prevalence and associated factors of low BMD in HIV patients. METHODS: Between 1 January 2015 and 31 December 2016, all patients aged 20 years or greater who sought for HIV care were included. BMD was measured by dual-energy X-ray absorptiometry. Multivariable analyses of the association with HIV disease status, treatment and anthropometric parameters were performed. Circulating fibroblast growth factor 23 and intact parathyroid hormone were measured. RESULTS: A total of 137 patients was included; their median age was 39 years old; 97.8% were treated with combination antiretroviral therapy (cART); Body mass index (BMI) was 21.97 kg/m2. Sixty-one patients (44.5%) showed low BMD (osteopenia and osteoporosis) based on the WHO criteria. The median BMD was -0.80 g/cm2 (IQR, -1.5 to -0.2). The prevalence rate of low BMD was 37% in those who were aged 20-29 years, 45.2% in those who were aged 30-39 years, 45.2% in those who were aged 40-49 years, 45.8% in those who were aged 50-59 years, and 53.8% in those who were aged ≧60 years. More than half of patients (50.4%, 69/137) were younger than 40 years. Compared with normal BMD group, the low BMD group has a higher proportion of secondary hyperparathyroidism (18.0% vs 5.3%, p: 0.026) and a lower median C-terminal FGF23 level (48.92 vs 62.61 pg/ml, p: 0.008). Univariate and multivariate analyses of the factors associated with low BMD. We found that only serum intact-parathyroid hormone (iPTH) > 69 pg/ml (OR, 3.86; 95% CI, 1.14-13.09) was statistically significant associated with low BMD in multivariate analysis. CONCLUSIONS: This cohort-based survey showed a high prevalence of low BMD among HIV-infected adults which included young-age patient in an university hospital. Secondary hyperparathyroidism was significantly associated with low BMD. There was no association between FGF23 and low BMD.

Micafungin is a novel anti-viral agent of chikungunya virus through multiple mechanisms.

The chikungunya virus (CHIKV) is a mosquito-borne virus that belongs to the genus Alphavirus, family Togaviridae. It is the cause of chikungunya fever in humans, which presents a serious global threat due to its high rate of contagion. The clinical symptoms of CHIKV include fever and persistent, severe arthritis. Micafungin has broad-spectrum fungicidal activity against Candida spp. is a promising echinocandin that was recently approved by the U.S. Food and Drug Administration (FDA) and has demonstrated activity against Candida and Aspergillus. Recent studies have demonstrated the antiviral activity of micafungin; however, the inhibitory effects against CHIKV have yet to be investigated. Our objectives in this study were to explore the antiviral effects of micafungin on CHIKV infection and to elucidate the potential molecular mechanisms of inhibition. We determined that micafungin has the ability to counter CHIKV-induced cytopathic effects. We further discovered that micafungin limits virus replication, release, cell-to-cell transmission, and also slightly affected virus stability during high doses treatment. The efficacy of micafungin was further confirmed against two clinical isolates of CHIKV and two alphaviruses: Sindbis virus (SINV) and Semliki Forest virus (SFV). Our findings suggest that micafungin has considerable potential as a novel inhibitor against the viral replication, and intracellular and extracellular transmission of CHIKV, and has a little effect on virus stability. Our findings also suggest that micafungin could have curative effects on other alphavirus infections.

Changing seroprevalence of hepatitis C virus infection among HIV-positive patients in Taiwan.

OBJECTIVE: The study aimed to describe the evolution of the seroprevalence of hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-positive patients included in two cohorts in Taiwan. METHODS: We retrospectively collected the information on demographic and clinical characteristics of 4,025 and 3,856 HIV-positive Taiwanese, who were aged 18 years or older at designated hospitals around Taiwan in 2004-2007, when an outbreak of HIV infection was occurring, and 2012-2016, when the outbreak was controlled with the implementation of harm reduction program, respectively. Comparisons of HCV seropositivity were made among different age and risk groups for HIV transmission between these two cohorts. RESULTS: The overall HCV seroprevalence of the 2004-2007 cohort and 2012-2016 cohort was 43.4% (1,288/2,974) and 18.6% (707/3,793), respectively (P<0.001). The HCV seroprevalence among injecting drug users (IDUs), though decreasing, was constantly high across the two cohorts, 96.4% and 94.0% (P = 0.02), respectively, and all age groups. In contrast, the corresponding figures among men who have sex with men (MSM) and heterosexuals in the two cohorts were 5.9% vs. 3.5% (P = 0.002) and 9.4% vs. 10.9% (P = 0.59), respectively. Among sexually transmitted HIV-positive patients, HCV seropositivity was significantly correlated with age (adjusted odds ratio [aOR], per 1-year increase, 1.03; 95% confidence interval [CI], 1.02-1.05) and a rapid plasma reagin (RPR) titer ≥1:8 (aOR, 1.58; 95% CI, 1.03-2.43) in a multivariate analysis including age, gender, route for HIV transmission, baseline CD4 count and plasma HIV RNA load, the presence of hepatitis B surface antigen, and an RPR titer ≥1:8. Compared with heterosexuals, the aOR for HCV seropositivity among MSM was 0.47 (95% CI, 0.31-0.72). CONCLUSIONS: HCV seroprevalence among HIV-positive patients in Taiwan decreased with time, probably related to the inclusion of younger adults and more non-IDUs, and remained high among IDUs. HCV seropositivity was associated with age and an RPR titer ≥1:8 among patients who acquired HIV through sexual contact.

Risk of fracture in transfusion-naïve thalassemia population: A nationwide population-based retrospective cohort study.

In thalassemia major or transfusion-dependent thalassemia patients, osteoporosis-related bone complications such as fracture events are common. However, no studies have investigated the risk of fracture in transfusion-naïve thalassemia population. Therefore, we conducted a longitudinal nationwide cohort study to determine whether this population has an increased risk of fracture. This nationwide, population-based cohort study analyzed data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending until the end of 2011. We identified cases with transfusion-naïve thalassemia and selected a comparison cohort that was frequency-matched according to age and year of diagnosis of thalassemia at a ratio of one subject with thalassemia to four subjects in the control group. We analyzed the risk of fracture events to occur in transfusion-naïve thalassemia cases by using Cox proportional hazards regression models. Totally, the study recruited 1369 transfusion-naïve thalassemia subjects and 5416 controls. We identified a total of 71 cases with fracture events within the thalassemia group and 204 within the control group. The overall risks for developing fracture events were 1.35-fold higher in transfusion-naïve thalassemia individuals than the comparison cohort after adjusting for age, sex and comorbidities. Most fracture events were observed in male transfusion-naïve thalassemia individuals rather than the normal population. In subgroup analysis, there was a 1.46-fold higher risk to develop upper-limb fracture in the thalassemia group than in the control groups. In conclusion, our long-term, cohort study results showed that there was a higher risk for the development of fractures in transfusion-naïve thalassemia individuals, particularly in male cases.

Evolution of hepatitis A virus seroprevalence among HIV-positive adults in Taiwan.

OBJECTIVES: The study aimed to describe the seroprevalence of hepatitis A virus (HAV) in HIV-positive adult patients in Taiwan between 2012 and 2016 and to examine the evolution of HAV seroprevalence between 2004-2007 and 2012-2016. METHODS: Clinical information and data of anti-HAV antibody results were collected from 2,860 antiretroviral-naïve HIV-positive Taiwanese aged 18 years or older who initiated combination antiretroviral therapy at 11 hospitals around Taiwan between 2012 and 2016 (2012-2016 cohort). A multivariate logistic regression model was applied to identify independent variables associated with HAV seropositivity. Comparisons of HAV seroprevalences and associated clinical characteristics were made between this 2012-2016 cohort and a previous cohort of 1580 HIV-positive patients in 2004-2007 (2004-2007 cohort). RESULTS: Of the 2,860 HIV-positive patients between 2012 and 2016, the overall HAV seropositivity rate was 21.2% (605/2860), which was independently associated with an older age (adjusted odds ratio [AOR], per 1-year increase, 1.13; 95% confidence interval [95% CI], 1.11-1.15) and co-infection with hepatitis B virus (AOR 1.44; 95% CI, 1.08-1.93). Residence in southern Taiwan (AOR 0.49; 95% CI, 0.34-0.72) was inversely associated with HAV seropositivity. The overall HAV seroprevalence in the 2012-2016 cohort was significantly lower than that in the 2004-2007 cohort (21.2% vs 60.9%, p<0.01). The decreases of HAV seropositivity rate were observed in nearly every age-matched group, which suggested the cohort effect on HAV seroepidemiology. However, among individuals aged 25 years or younger, the HAV seropositivity rate increased from 3.8% (2/52) in the 2004-2007 cohort to 8.5% (50/587) in the 2012-2016 cohort, with 95.4% (560/587) being MSM in this age group of the latter cohort. CONCLUSIONS: HAV seroprevalence has decreased with time among HIV-positive adults in Taiwan. The cohort effect has increased the number of young HIV-positive patients that are susceptible to HAV infection in a country without nationwide childhood vaccination program against HAV.

Trends and outcomes of late initiation of combination antiretroviral therapy driven by late presentation among HIV-positive Taiwanese patients in the era of treatment scale-up.

OBJECTIVES: The international and national HIV treatment guidelines in 2016 have focused on scaling up access to combination antiretroviral therapy (cART). We aimed to assess the trends and treatment outcomes of late cART initiation in Taiwan. METHODS: Between June 2012 and May 2016, we retrospectively included antiretroviral-naive HIV-positive adults who initiated cART. Late initiation was defined as when cART was initiated in patients with a CD4 count <200 cells/mm3 or having experienced AIDS-defining illnesses. The treatment outcomes were assessed up to 6 months after starting cART. RESULTS: We included 3655 HIV-positive patients, and the majority of the patients were male (95.4%) with a median age of 31 years and initiated non-nucleoside reverse-transcriptase inhibitor-containing regimens (87.0%). The median CD4 count at cART initiation increased from 207 cells/mm3 in 2012 to 298 cells/mm3 in 2016, and the overall proportion of late cART initiation decreased from 49.1% in 2012 to 29.0% in 2016 (P for trend <0.001). Late cART initiation mainly resulted from late presentation for HIV care and was associated with older age (per 1-year increase, adjusted odds ratio [AOR], 1.05; 95% CI, 1.04-1.06), HBsAg seropositivity (AOR, 1.31; 95% CI, 1.04-1.64), HIV care in central and southern Taiwan, initiating cART in earlier year, non-intravenous drug users (AOR, 1.96; 95% CI, 1.33-2.86), and negative hepatitis C serostatus (AOR, 1.47; 95% CI, 1.04-2.08). Compared with non-late initiators, late initiators had a higher rate of all-cause mortality (1.7% vs. 0.3%) and regimen modification due to virological failure (7.1% vs. 2.6%). The predicting factors of all-cause mortality were late cART initiation (adjusted hazard ratio [AHR], 5.40; 95% CI, 2.14-13.65) and older age (AHR, 1.06; 95% CI, 1.03-1.10). CONCLUSIONS: While the proportion of late cART initiation decreased over time in Taiwan, late initiation remained in a substantial proportion of HIV-positive patients. The late initiators had higher risk for poor outcomes. The need for strategies to earlier detection of HIV infection and expediting cART initiation should be highlighted, especially among the older population.

Safety and immunogenicity of an inactivated cell culture-derived H7N9 influenza vaccine in healthy adults: A phase I/II, prospective, randomized, open-label trial.

BACKGROUND: We conducted a phase I/II clinical trial to evaluate the safety and immunogenicity of a Madin-Darby canine kidney (MDCK) cell-grown inactivated H7N9 influenza vaccine for pandemic preparedness purposes. METHODS: Between April 7, 2015 and May 27, 2016, healthy adults aged 20-60years were enrolled sequentially in phase I (n=40) and phase II (n=160) from three hospitals in Taiwan and randomized to receive 2 doses of whole-virus H7N9 vaccine (15 or 30µg hemagglutinin antigen (HA) with or without an aluminum hydroxide adjuvant) at 21-day intervals. Safety up to 180days and changes in hemagglutinin inhibition (HI) titers at 21days after each vaccination were determined. RESULTS: Of the 200 randomized subjects, 193 (96.5%) received 2 doses of the study vaccine and were included in the intention-to-treat analysis for safety, and 190 (95%) were included in the per-protocol analysis for immunogenicity. Most adverse events were mild and transient; no death or vaccine-related serious adverse events were reported. Overall, higher immune responses were observed in the groups administered with 30µgHA formulation than in the other two groups administered with 15µgHA formulation. The highest immune response was observed in subjects who received 2 doses of the adjuvanted vaccine containing 30µgHA with HI titer, seroprotection rate, seroconversion rate, and seroconversion factor of 36.2, 64.6%, 64.6% and 5.7, respectively. CONCLUSIONS: Our study demonstrated that the H7N9 influenza vaccine containing 30µgHA with aluminum hydroxide adjuvant was immunogenic and safe in adults aged 20-60years. CLINICALTRIALS.GOV identifier: NCT02436928.