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OBJECTIVE Type 1 diabetes (T1D) has been linked to enterovirus infection in small population-based epidemiological studies. We investigated the secular relationship of T1D incidence with enterovirus infection and enterovirus species using nationwide population-based analysis. RESEARCH DESIGN AND METHODS We accessed the National Health Insurance Research Database of Taiwan to identify T1D and enterovirus infection cases from 2001 to 2015. Enterovirus serotype isolation rates were obtained from the nationwide laboratory surveillance systems. Negative binomial regression models assessed the incidence trend, and extended Cox proportional hazards models analyzed the association of enterovirus infection with T1D incidence. Spearman correlation coefficients evaluated the correlation between T1D incidence and circulating enterovirus species. RESULTS T1D incidence rates in youth younger than 20 years were 6.30 and 5.02 per 100,000 person-years in 2001 and 2015 (P = 0.287), respectively. T1D incidence increased significantly in children aged 0–6 years (P < 0.001) but decreased in adolescents aged 13–19 years (P = 0.011). The T1D risk in children aged 0–6 years with enterovirus infection was significantly higher than that in noninfected subjects (hazard ratio 1.46; 95% CI 1.35–1.58; P < 0.001). Additionally, TID incidence in children aged 0–6 years was significantly correlated with the isolation rates of coxsackievirus A species (r = 0.60; P = 0.017), but no association was found beyond the age of 7. CONCLUSIONS We demonstrated that T1D incidence increased in children aged 0–6 years but decreased in adolescents aged 13–19 years in Taiwan. Enterovirus-infected subjects younger than 7 years had a higher risk of T1D than noninfected subjects.

Anemia is associated with severe outcomes in adult community-acquired pneumonia (CAP), but few studies investigated its association with pediatric CAP. Hence, we tried to delineate the association of anemia with the clinical outcomes of CAP in children.This retrospective cohort study was conducted from 2010 to 2019 in a medical center. Inpatients aged 6 months to 17 years who were diagnosed with CAP and without major underlying diseases were included. The subjects' clinical data within 24 h of admission and clinical outcomes were collected. We accessed the rates of adverse outcomes and the adjusted odds ratios (ORs) of these outcomes between anemic and nonanemic patients, as well as among patients with different types of anemia.In this study of 3601 patients, the prevalence of anemia was 11.6% (418/3601). Anemic patients had higher rates of intensive care (16.8% vs. 3.6%; p 0.001), endotracheal intubation (11.0% vs. 1.3%; p 0.001), and empyema (8.6% vs. 0.6%; p 0.001) than nonanemic patients. In addition, anemia was independently associated with intensive care (adjusted OR, 3.00; 95% confidence interval [CI], 2.03-4.42), endotracheal intubation (adjusted OR, 3.79; 95% CI, 2.17-6.63), and empyema (adjusted OR, 4.72; 95% CI, 2.30-9.69). Iron-deficiency anemia (IDA) and normocytic anemia were associated with these adverse outcomes but not with anemia due to thalassemia trait.Anemia is a biomarker associated with poor outcomes in pediatric CAP, and patients with IDA or normocytic anemia should be carefully monitored and managed since they may have higher disease severity.

This study uses an intersectionality lens to understand the inequality of medical use at the intersection of age and air pollution. Using national databases from Taiwan, the results show that the increase of the level of air pollution and age is related to higher percentage of high medical use. Through stratified analysis, we found that there is no significant difference in medical use among different age groups in low AQI (Air Quality Index) areas, Yet, in areas with increasing amounts of polluted air, the elderly have a significantly higher percentage in frequent medical use. Our results show that the elderly people are more susceptible to air pollution, and suggest that, to protect their health and reduce the use of medical care, not only is there a need to reduce air pollution, but also maintain the annual average AQI level to under the value of 50.

An abnormal growth of Cu3Sn through the grain boundaries of Cu6Sn5 formed in Ni/Sn/Cu ternary diffusion couples is reported in this study. The Ni/Sn/Cu diffusion couples are prepared by thermal compression bonding, with the Sn thickness controlled at 10 μm. The diffusion couples are aged at 200 °C for different periods of time. Due to the thinness of the initial Sn layer, the entire Sn layer ware converted into Cu6Sn5 and Cu3Sn only after 52 h or aging. At this stage, both compounds exhibit the layered structure. Afterward, as the reaction continues, Cu3Sn grows thicker at the expense of Cu6Sn5. Interestingly Cu3Sn now preferably grows along the grain boundaries of Cu6Sn5. The rationalization for this abnormal growth pattern is discussed.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCV) contribute to about 10-15% global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infection have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, KSHV, and HTLV-1 had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA interference-based therapies for treating HPV-associated infection or cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies in a real-world setting are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCV) contribute to about 10-15% global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infection have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, KSHV, and HTLV-1 had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA interference-based therapies for treating HPV-associated infection or cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies in a real-world setting are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

The reaction within Ni/Sn/Cu microjoints has been investigated with a 10 μm initial thickness of Sn so that Sn was quickly consumed in the early stage of the reaction, transforming the joints into full intermetallic joints. Accordingly, the emphasis of the present study is on the materials interactions in such full intermetallic joints. Ni/Sn/Cu sandwiches were prepared by thermal compression bonding. High-temperature storage tests were conducted at 150°C, 180°C, and 200°C for different time periods. The hardness and Young’s modulus of the intermetallic joints were measured using nanoindentation. The key finding of this study is that, once Sn was exhausted, the originally planar (Cu,Ni)3Sn grew preferably along the grain boundary of (Cu,Ni)6Sn5, creating a highly nonuniform (Cu,Ni)3Sn growth front. Both the hardness and elastic modulus increased with the Ni concentration in the intermetallics.

Enterovirus 71 (EV71) is one of the major pathogens that cause severe enteroviral infections. Our aim was to study the behavioral and household risk factors for its serious complications.Between May 2011 and November 2012, we enrolled children who had symptoms of EV71 infection from six hospitals in Taiwan. The caregivers of each patient were interviewed to determine their hand hygiene habits in relation to EV71 infection. The severity of EV71 infection was classified as follows: Stage 1, hand-foot-mouth disease or herpangina; Stage 2, meningitis or myoclonic jerk; Stage 3A, encephalitis; Stage 3B, cardiopulmonary failure. Stages 2 to 3B were defined as severe EV71 infection. Children with Stages 3A and 3B infection were designated as the critical group.A total of 399 patients had laboratory-confirmed EV71 infection. Three risks factors were associated with the different degrees of severity in EV71 infection. Children2 years old had much greater risks for severe EV71 infection [odds ratio (OR) 1.8; 95% confidence interval (CI), 1.2-2.8], delayed medical evaluation for critical infection (OR 9.4; 95% CI, 3.6-24.1), and developmental retardation for cardiopulmonary failure (OR 8.3; 95% CI, 2.0-33.7). Among all the habits and household factors, caregivers in the critical group had a significantly lower rate in terms of cleaning the faucet after washing their hands (OR 2.63; 95% CI, 1.14-6.08).Children2 years old, developmental retardation, and delayed medical intervention were associated with severe EV71 infection. Cleaning water faucets after hand washing was a protective habit that reduced the risk of complications.

This protocol describes the process forthe neutralizing antibody test of EV-D68.

Background During recent 20 years, enterovirus 71 (EV71) has emerged as a major concern among children, particularly in the Asia-Pacific region. To understand current EV71 serostatus, to find risk factors associated with EV71 infection and to establish future EV71 vaccine policy, we performed a seroepidemiology study in Taiwan in 2017. Methods After informed consent was obtained, we enrolled preschool children, 6–15-year-old students, 16–50-year-old people. They received a questionnaire and a blood sample was collected to measure the EV71 neutralization antibody. Results Altogether, 920 subjects were enrolled with a male-to-female ratio of 1.03. The EV71 seropositive rate was 10% (8/82) in infants, 4% (6/153) in 1-year-old children, 8% (7/83) in 2-year-old children, 8% (13/156) in 3–5-year-old children, 31% (38/122) in 6–11-year-old primary school students, 45% (54/121) in 12–15-year-old high school students and 75% (152/203) in 16-50-year-old people. Risk factors associated with EV71 seropositivity in preschool children were female gender, having siblings, more siblings, and contact with herpangina or hand-foot-and-mouth disease. The risk factor with EV71 seropositivity in 16–50-year-old people was having children in their families in addition to older age (p

Background Early life stress is a significant environmental factor for Major Depressive Disorder (MDD). Recent animal studies have shown that the long-term effect of early life stress might influence the combination of intestinal microbiota in the adult. The present study examined the association between early life stress and the microbiota features in the fecal sample of adult participants. Methods We recruited 7 MDD patients and 11 healthy controls, and the Childhood Trauma Questionnaire was used to examine the status of each dimension of childhood maltreatment. The fecal samples were examined by Illumina Miniseq or Miseq platform for 16 s rRNA sequencing of microbiota features. Linear discriminant analysis effect size (LEfSe) was applied to test associations between early life stress and microbiota. Results We used the average score of sexual abuse by all participants as a cut-off point. The abundance of Phascolarctobacterium, Deltaproteobacteria, Bilophila, Thiothrix, Thiotrichaceae, and Thiotrichales significantly increased in the adult participants with childhood trauma of sexual abuse. After adjusted for MDD status, the groups of microbiota still significantly increased in abundance of Bilophila, Thiothrix, Thiotrichaceae, and Thiotrichales. Discussion The replication data with 15 MDD patients and 25 healthy controls is underway. Our study revealed the association between the early life stress and the microbiota features.

Background Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation. Methods A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication. Results Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10 −4 , D′ = 1 with rs3749034) with BD in the Taiwanese dataset. Limitations The present study considered common genetic variants only. In addition, we only used a 293 T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes. Conclusions Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants.

Soldering reactions in very confined spaces are becoming an increasingly important issue owing to their applications for micro-joints in three-dimensional integrated circuits. Gold embrittlement is becoming relevant again as soldering joints become smaller. In this study, the maximum allowable Au content in micro-joints is investigated, and it was determined to be 1.3 wt.%. Direct Cu doping in solder can prevent the formation of AuSn4. Nevertheless, direct Cu doping may not be effective if the Au concentration is too high. It is demonstrated that using Cu under bump metallization can completely inhibit the formation of AuSn4 and eliminate the risk of gold embrittlement.

The solid-state reactions under confined space between Cu substrate and Sn and Sn–Ag solders are systematically investigated, with the objective of providing fundamental data that are critical to the design of robust microjoints for chip-stacking applications. Sandwich structures of Cu/Sn/Cu and Cu/Sn3.5Ag/Cu are prepared by thermal compression bonding. The thickness of Sn and Sn3.5Ag layer is controlled at 10 μm. High temperature storage tests are conducted at 120 °C, 150 °C, 180 °C, and 200 °C for different time periods. Unlike the well-known void formation in the Ni/Sn/Ni system, there is no such void at all in the Cu/Sn/Cu system. The addition of Ag consistently slows down the growth kinetics of intermetallics. The time-to-impingement of intermetallics is established for the first time for both systems under solid-state reactions.

The oxidation resistance of two important surface finishes, electroless Ni/immersion Au (ENIG) and electroless Ni/electroless Pd/immersion Au (ENEPIG), is studied. Auger electron spectroscopy and X-ray photoelectron spectroscopy analyses show that ENEPIG is more oxidation resistant. The oxidized species of Ni diffuse through the Au grain boundaries. The mechanism for this better performance is that the Pd layer has an amorphous structure. The amorphous Pd layer is able to inhibit the out-diffusion of Ni atoms through high-diffusivity paths.

Experiments are carried out to measure the volume shrinkage during solid-state reaction in micro-joints for three-dimensional integrated circuit applications. Surface profilometer is employed to measure the volume shrinkage for the reaction between Ni and Sn. The shrinkage is correlated with the microstructural evolution during the reaction. It is found that the volume shrinkage is released through both joint height reduction and void formation. The resulting internal stress and the void formation might post potential reliability issues.

Background: Tumor-infiltrating leukocytes (TILs) are immune cells surrounding tumor cells, and several studies have shown that TILs are potential survival predictors in different cancers. However, few studies have dissected the differences between hepatitis B- and hepatitis C-related hepatocellular carcinoma (HBV&minus, HCC and HCV&minus, HCC). Therefore, we aimed to determine whether the abundance and composition of TILs are potential predictors for survival outcomes in HCC and which TILs are the most significant predictors. Methods: Two bioinformatics algorithms, ESTIMATE and CIBERSORT, were utilized to analyze the gene expression profiles from 6 datasets, from which the abundance of corresponding TILs was inferred. The ESTIMATE algorithm examined the overall abundance of TILs, whereas the CIBERSORT algorithm reported the relative abundance of 22 different TILs. Both HBV&minus, HCC were analyzed. Results: The results indicated that the total abundance of TILs was higher in non-tumor tissue regardless of the HCC type. Alternatively, the specific TILs associated with overall survival (OS) and recurrence-free survival (RFS) varied between subtypes. For example, in HBV&minus, HCC, plasma cells (hazard ratio [HR] = 1.05, 95% CI 1.00&ndash, 1.10, p = 0.034) and activated dendritic cells (HR = 1.08, 95% CI 1.01&ndash, 1.17, p = 0.03) were significantly associated with OS, whereas in HCV&minus, HCC, monocytes (HR = 1.21) were significantly associated with OS. Furthermore, for RFS, CD8+ T cells (HR = 0.98) and M0 macrophages (HR = 1.02) were potential biomarkers in HBV&minus, HCC, whereas neutrophils (HR = 1.01) were an independent predictor in HCV&minus, HCC. Lastly, in both HBV&minus, HCC, CD8+ T cells (HR = 0.97) and activated dendritic cells (HR = 1.09) had a significant association with OS, while &gamma, delta T cells (HR = 1.04), monocytes (HR = 1.05), M0 macrophages (HR = 1.04), M1 macrophages (HR = 1.02), and activated dendritic cells (HR = 1.15) were highly associated with RFS. Conclusions: These findings demonstrated that TILs are potential survival predictors in HCC and different kinds of TILs are observed according to the virus type. Therefore, further investigations are warranted to elucidate the role of TILs in HCC, which may improve immunotherapy outcomes.

Background Growing evidence suggests the link between gut microbiota and mood regulation. While previous studies reported several microbiota targets for Major Depressive Disorder (MDD), the influence of dietary patterns is not considered. The current study aims to identify microbiota targets for MDD depression in two independent Taiwanese datasets while taking nutrient elements into consideration. Methods We separately analyzed fecal samples from two independent datasets. The discovery set consisted of 9 MDD patients and 11 healthy controls while replication set comprised of 15 MDD patients and 25 healthy controls. Illumina Miniseq or Miseq platform were applied for 16 s rRNA sequencing. We further assessed food frequency questionnaires and Beck depression inventory to obtain the information of nutrients and depressive status. We applied linear discriminant analysis effect size (LEfSe) to test associations between depression and microbiota and adjusted for nutrient status. Results In the discovery data, the microbiota exhibited significant group differences in genus level, including increased abundance of Bilophila and Gillisia, and decreased abundance of Clostridium. The results remained significant after adjusted levels of carbohydrates, protein and fat intake. The replication study is underway. Discussion Our results revealed novel targets to be associated with depression and are independent of dietary influences. These results awaiting replication and further validation for depression.

Dissolution of cathode metallization is one of the key degradation processes for solder interconnects under electron current stressing. Very recently, several studies have shown that this dissolution often results in a highly serrated interface, but little is known about how the serrated interface develops and what mechanism contributes to this intriguing microstructural feature. This paper presents detailed observations from a purposely designed experiment to uncover the responsible mechanism. These observations reveal that a pronounced and unstable grain boundary grooving between Cu 6 Sn 5 grains occurs before the serrated cathode starts to develop. This grooving process is driven by preferential dissolution at the grain boundaries, a process similar to the formation of scallop-type Cu 6 Sn 5 between molten solder and Cu. Furthermore, the diffusion and reaction are more significant at the valley of the grooves, which increases the local consumption rate of Cu. This non-uniform consumption of Cu eventually leads to a serrated cathode interface.

A region on chromosome 4q25 has recently been highlighted as linked to hepatocellular carcinoma (HCC). In this study, we performed a family-based association analysis with 67 single-nucleotide polymorphisms (SNPs) to map this linkage region in 240 families with HCC, 212 (88.3%) of which were ascertained through hepatitis B virus surface antigen (HBsAg)-positive index cases. Individual SNP analysis with correction for multiple testing identified 10 SNPs in two correlated haplotype blocks, located in or around the 3'-phosphoadenosine 5'-phosphosulfate synthetase-1 (PAPSS1) gene (all P-values:0.0075). Our linkage data and GIST (Genotype identity-by-descent sharing test) indicate that 6 of these 10 SNPs contributed to the linkage signal. The haplotype block of the strongest association with HCC extended from the intron 5 to the 3'-flanking region of PAPSS1; multiple consecutive three-SNP haplotypes in this region were significant. The most significant haplotype showed odd ratios of 3.41 (95% confidence interval (CI)=1.36-8.53) for homozygous individuals in a case-unaffected sibling analysis. This haplotype also revealed an association with elevated serum alpha-fetoprotein and with poor survival in familial cases and an independent series of HBsAg-positive cases with small tumor present at the time of hospital admission. These results implicate PAPSS1 as a candidate HCC-susceptibility gene in hepatitis B carriers.

Background and aims: To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case–control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988–1992. Methods: The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up. Results: Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants. Conclusions: HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.

Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (

Background: Although chronic infection with hepatitis B virus (HBV) has been established as a cause of hepatocellular carcinoma (HCC), the roles of viral load and HBV genotype remain unclear. Methods: From 1988 through 1992, baseline blood samples were collected from 4841 Taiwanese men who were HBV carriers but had not been diagnosed with HCC. We used real-time polymerase chain reaction assays of plasma DNA samples to quantify HBV DNA levels (a measure of viral load) and determine HBV genotypes for 154 case patients who were diagnosed with HCC during 14 years of follow-up and 316 control subjects. Unconditional logistic regression was used to assess odds ratios (ORs) of HCC for HBV-related factors. All statistical tests were two-sided. Results: The risk of HCC increased with increasing HBV viral load (adjusted OR for the highest versus the lowest quintile of HBV DNA copies/mL = 7.26, 95% confidence interval [CI] = 3.54 to 14.89; P trend

Recently, three-dimensional integrated circuit (3D IC) integration technology consisting of TSV and micro joints has been viewed as one of the very promising solutions to go beyond Moore's law. Typical solder joints for 3D IC stacking technique under development today has a solder volume about 1000 μm 3 , which is roughly 1/500 that of a conventional flip-chip solder joint with usually an 100 μm in diameter. One well-perceived effect of such a small solder volume is the solder joint would have very high possibility to end in a relatively large fraction of intermetallic compounds (IMCs) after common reflowing or thermal compression bonding process. Under this circumstance, instead of solder, the mechanical properties of IMCs and other reaction-induced microstructural changes and characteristics will undoubtedly play dominant roles on the reliability of the micro joints. In this study, solid-state interfacial reactions under a very confined space between Cu and Sn, Sn-Ag, Sn-Bi, Sn-Zn solders are systematically investigated. The objective of this paper is not merely to propose and identify some critical reliability concerns arising from interfacial reactions but to provide essential data for microelectronic packaging industry to the design of sturdy enough micro solder joints for multichip stacking applications. Sandwich structures of Cu/Solder/Cu are fabricated through chip-to-chip thermal compression bonding process. The thickness of the solder layer in this study is well-controlled at 10 μm. High temperature storage tests are conducted by isothermal aging at 120 °C, 150 °C, 180 °C, and 200 °C for different time periods, respectively. Issues to be discussed in this paper include (a) Impingement behavior of IMC grains after solid-state isothermal aging, (b) Rise of concentrations of minor inert alloying constituents in low solder volume joint, (c) Promising approach to reduce the growth rate of Cu-Sn reactants within limited solder volume joint. These critical issues will be proposed and discussed through experimental evidence, and the implications based on these finding will be discussed as well.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), and Epstein-Barr virus (EBV) contribute to about 10-15 % global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infections have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell lymphotropic virus type 1 (HTLV-1) had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA-interference-based therapies for treating HPV-associated cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), and Epstein-Barr virus (EBV) contribute to about 10-15 % global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infections have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell lymphotropic virus type 1 (HTLV-1) had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA-interference-based therapies for treating HPV-associated cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

Bipolar disorder (BPD) is a complex psychiatric trait with high heritability. Despite efforts through conducting genome-wide association (GWA) studies, the success of identifying susceptibility loci for BPD has been limited, which is partially attributed to the complex nature of its pathogenesis. Pathway-based analytic strategy is a powerful tool to explore joint effects of gene sets within specific biological pathways. Additionally, to incorporate other aspects of genomic data into pathway analysis may further enhance our understanding for the underlying mechanisms for BPD. Patterns of DNA methylation play important roles in regulating gene expression and function. A commonly observed phenomenon, allele-specific methylation (ASM) describes the associations between genetic variants and DNA methylation patterns. The present study aimed to identify biological pathways that are involve in the pathogenesis of BPD while incorporating brain specific ASM information in pathway analysis using two large-scale GWA datasets in Caucasian populations. A weighting scheme was adopted to take ASM information into consideration for each pathway. After multiple testing corrections, we identified 88 and 15 enriched pathways for their biological relevance for BPD in the Genetic Association Information Network (GAIN) and the Wellcome Trust Case Control Consortium dataset, respectively. Many of these pathways were significant only when applying the weighting scheme. Three ion channel related pathways were consistently identified in both datasets. Results in the GAIN dataset also suggest for the roles of extracellular matrix in brain for BPD. Findings from Gene Ontology (GO) analysis exhibited functional enrichment among genes of non-GO pathways in activity of gated channel, transporter, and neurotransmitter receptor. We demonstrated that integrating different data sources with pathway analysis provides an avenue to identify promising and novel biological pathways for exploring the underlying molecular mechanisms for bipolar disorder. Further basic research can be conducted to target the biological mechanisms for the identified genes and pathways.

Prognosis of hepatocellular carcinoma (HCC) is generally poor. The role of modifiable lifestyle factors on HCC survival has been less studied. To examine whether prediagnosis smoking and alcohol affected HCC survival stratified by viral etiology, we conducted a prospective cohort study of 2,273 (1990 with viral hepatitis and 283 without) incident HCC cases aged 20-75 years who were enrolled between 1997 and 2004 from a Taiwanese multicenter study, and followed up through 2007. Information on habitual smoking and alcohol consumption was obtained at baseline through personal interview. After follow-up to a maximum of 10 years, 1,757 participants died and 1,488 (84.7%) were attributed to HCC. Prediagnosis smoking and alcohol worsened prognosis independent of each other and clinical predictors. The effects of both risky behaviors were limited to viral hepatitis-related HCC and more profound among those with early-stage HCC. Risk for HCC-specific mortality increased with increasing pack-years smoked and ethanol intake (all p < 0.001 for trend), with an additive effect shown for the two habits [hazard ratio (HR) for alcohol ≥ 46.2 g/day and ≥ 10 pack-years = 1.72, 95% confidence interval (CI) = 1.45-2.05]. For either habit, cessation reduced HCC-specific mortality, but a significant mortality benefit occurred 10 years after abstinence (quitting smoking ≥ 10 years vs. continuing smokers: HR = 0.77, 95% CI = 0.61-0.97; quitting drinking ≥ 10 years vs. continuing drinkers: HR = 0.74, 95% CI = 0.56-0.98). In conclusion, among patients with viral hepatitis-related HCC, prediagnosis smoking and alcohol have a deleterious effect on HCC survival. Quitting smoking or drinking alcohol could reduce the excess risk, but only after a long interval of cessation.

The present study aims to reveal new issues relating to interfacial reactions arising from low solder volume in 3D IC packaging. Sandwich structures of Ni/Sn/Ni and Ni/SnAg/Ni were prepared by a general electroplating process. A high-temperature storage test was conducted by isothermal aging at 150, 180 and 200 °C. Microstructure characterizations revealed that initially a whisker-like Ni-Sn phase was located at the Ni/Sn interface in the as-plated condition. According to previous research, these whiskers are believed to be NiSn 4 . However, most of these NiSn 4 whiskers were no longer visible after 24 h of aging. Throughout the aging process, the main interfacial IMC was Ni 3 Sn 4 . Grains of Ni 3 Sn 4 growing from opposite interfaces started to impinge on each other after aging at 150 °C for merely 72 h. When the aging time reached 240 h, the Ni 3 Sn 4 occupied most of the interfacial area. Consequently, residual Sn formed islands located in between Ni 3 Sn 4 grains. The growth of Ni 3 Sn 4 followed parabolic kinetics during reactions. The parabolic constants are different from cases where the solder volumes are large but contain the same order of magnitude. IMC growth curves fitted a power-law relationship with exponents between 0.3 and 0.5, which suggests the growth of Ni 3 Sn 4 was controlled by both volume diffusion and grain ripening. Regarding the Ni/SnAg/Ni reaction, NiSn 4 whickers that formed during the electroplating process also shrank and disappeared after 24 h of aging. Afterward, the only IMCs were Ni 3 Sn 4 and Ag 3 Sn. The parabolic constant of Ni 3 Sn 4 growth is similar to values in the literature, regardless of the solder volume in reactions. The power-law exponent of Ni 3 Sn 4 growth is calculated as 0.27, which may be greatly a response to a process controlled by grain-ripening. The Ag 3 Sn IMC coarsened with prolonged aging and was ultimately located in the middle of the interface. Explanations of the microstructure and growth kinetics of the IMCs are presented and discussed.

High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV.We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years.After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother-child pairs. Heritability accounted for approximately 30% (p0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p0.0001) in unrelated individuals.HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.

Purpose To determine prospectively whether body-mass index (BMI) is associated with liver-related morbidity and mortality among male hepatitis B virus (HBV) carriers. Patients and Methods We performed a prospective study of 2,903 male HBV surface antigen–positive government employees who were free of cancer at enrollment between 1989 and 1992. Main outcome measures included ultrasonography, biochemical tests, incident hepatocellular carcinoma (HCC), and liver-related death. Results During mean follow-up of 14.7 years, 134 developed HCC and 92 died as a result of liver-related causes. In Cox proportional hazards models adjusting for age, number of visits, diabetes, and use of alcohol and tobacco, the hazard ratios for incident HCC were 1.48 (95% CI, 1.04 to 2.12) in overweight men (BMI between 25.0 and 29.9 kg/m2) and 1.96 (95% CI, 0.72 to 5.38) in obese men (BMI ≥ 30.0 kg/m2), compared with normal-weight men (BMI between 18.5 and 24.9 kg/m2). Liver-related mortality had adjusted hazard ratios of 1.74 (95% CI, 1.15 to 2.65) in overweight men and 1.50 (95% CI, 0.36 to 6.19) in obese men. Excess BMI was also associated with the occurrence of fatty liver and cirrhosis detected by ultrasonography, as well as elevated ALT and γ-glutamyltransferase (GGT) activity during follow-up. The association of BMI with GGT was stronger than with ALT, and elevated GGT activity and cirrhosis were the strongest predictors for incident HCC and liver-related death. Conclusion This longitudinal cohort study indicates that excess body weight is involved in the transition from healthy HBV carrier state to HCC and liver-related death among men.

Little is known about the longitudinal course of hepatitis B virus (HBV) load and its relationship with the development of hepatocellular carcinoma (HCC). We conducted a case-cohort study nested within a cohort of 2874 HBV surface antigen-positive male Taiwanese government employees aged 30 years or older. HBV genotype and DNA levels (i.e. viral load) were tested using polymerase chain reaction-based assays on plasma samples from 112 cases and 1031 non-cases. Prediagnostic plasma levels of HBV DNA were measured in multiple samples collected from each man (total 7706 samples), taken over periods of up to 16 years before diagnosis. Baseline viral load influenced HBV genotype-specific HCC risks and predicted the persistence of high viral load (/=4.39 log copies/ml) that can cause HCC. Moderate to high tracking of viral load was observed within 9 years. Hepatitis B e antigen (P0.0001), genotype C HBV infection (P = 0.0369) and longitudinal alanine aminotransferase (ALT) elevation (defined as ALT abnormality in/=50% of the visits) (P = 0.0005) were positively related to longer duration of persistence for high viral load. After multivariate adjustment, HBV genotype C [odds ratio (OR) = 5.97, 95% confidence interval (CI) = 3.44-10.34], high viral load detected at/=50% of the visits (compared with sustained low viral load: OR = 5.04, 95% CI = 2.31-11.00) and longitudinal ALT elevation (compared with sustained normal ALT levels: OR = 2.84, 95% CI = 1.46-5.51) accounted for 43.5, 57.2 and 24.9% of HCCs, respectively. The results suggest that maintenance of viral load4.39 log copies/ml was associated with sustained normalization of ALT levels and decreased risk of HCC.

Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3-28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3-28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned approximately 873 kb away from D4S3240 was associated with HCC, with P=0.0074.

Excessive cathode dissolution due to high current densities is investigated. Such excessive dissolution is one of the key electromigration-induced degradation processes in micro systems, and exhibits a distinctive serrated morphology. In this study, Cu cathode and Cu anode connected with Sn is stressed at a 4.5 × 104 A/cm2 current density for time as long as 1500 h. Careful sequential micro polishing is able to establish for the first time that the serrated cathode interface in fact is the expression of rod-like indentations in three-dimensional morphology. This unique morphology supports the proposition that fast Cu diffusion through Cu6Sn5 grain boundaries is the root cause for this excessive dissolution.

The purpose of this study was to estimate both cross-sectional sibling recurrence risk ratio (λ s ) and lifetime λ s for the metabolic syndrome and its individual components over time among sibships in the prospectively followed-up cohorts provided by the Genetic Analysis Workshop 13. Five measures included in the operational criteria of the metabolic syndrome by the Adult Treatment Panel III were examined. A method for estimating sibling recurrence risk with correction for complete ascertainment was used to estimate the numerator, and the prevalence in the whole cohort was used as the denominator of λ s . Considerable variability in the λ s was found in terms of different time-points for the cross-sectional definition, the times of fulfilling the criterion for lifetime definition, and different components. Obesity and hyperglycemia had the highest cross-sectional λ s of the five components. Both components also had the largest slopes in the linear trend of the lifetime λ s . However, the magnitudes of the lifetime λ s were similar to that of the mean cross-sectional λ s , which were