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Social Assistive Robotics is increasingly being used in care settings to provide psychosocial support and interventions for the elderly with cognitive impairments. Most of these social robots have provided timely stimuli to the elderly at home and in care centres, including keeping them active and boosting their mood. However, previous investigations have registered shortcomings in these robots, particularly in their ability to satisfy an essential human need: the need for companionship. Reports show that the elderly tend to lose interests in these social robots after the initial excitement as the novelty wears out and the monotonous familiarity becomes all too familiar. This paper presents our research facilitating conversations between a social humanoid robot, Nadine, and cognitively impaired elderly at a nursing home. We analysed the effectiveness of human-humanoid interactions between our robot and 14 elderly over 29 sessions. We used both objective tools (based on computer vision methods) and subjective tools (based on observational scales) to evaluate the recorded videos. Our findings showed that our subjects engaged positively with Nadine, suggesting that their interaction with the robot could improve their well-being by compensating for some of their emotional, cognitive, and psychosocial deficiencies. We detected emotions associated with cognitively impaired elderly during these interactions. This study could help understand the expectations of the elderly and the current limitations of Social Assistive Robots. Our research is aligned with all the ethical recommendations by the NTU Institutional Review Board., (© The Author(s) 2021.)

Background: We validated the Data collection on Adverse events of anti-HIV Drugs (D:A:D) full-risk and short-risk score models for chronic kidney disease (CKD) in the Asian HIV cohorts., Settings: A validation study among people living with HIV (PLHIV) aged ≥18 years among the cohorts in the Asia-Pacific region., Methods: PLHIV with a baseline estimated glomerular filtration rate > 60 mL/min/1.73 m were included for validation of the D:A:D CKD full version and short version without cardiovascular risk factors. Those with <3 estimated glomerular filtration rate measurements from baseline or previous exposure to potentially nephrotoxic antiretrovirals were excluded. Kaplan-Meier methods were used to estimate the probability of CKD development. The area under the receiver operating characteristics was also used to validate the risk score., Results: We included 5701 participants in full model {median 8.1 [interquartile range (IQR) 4.8-10.9] years follow-up} and 9791 in short model validation [median 4.9 (IQR 2.5-7.3) years follow-up]. The crude incidence rate of CKD was 8.1 [95% confidence interval (CI): 7.3 to 8.9] per 1000 person-years in the full model cohort and 10.5 (95% CI: 9.6 to 11.4) per 1000 person-years in the short model cohort. The progression rates for CKD at 10 years in the full model cohort were 2.7%, 8.9%, and 26.1% for low-risk, medium-risk, and high-risk groups, and 3.5%, 11.7%, and 32.4% in the short model cohort. The area under the receiver operating characteristics for the full-risk and short-risk score was 0.81 (95% CI: 0.79 to 0.83) and 0.83 (95% CI: 0.81 to 0.85), respectively., Conclusion: The D:A:D CKD full-risk and short-risk score performed well in predicting CKD events among Asian PLHIV. These risk prediction models may be useful to assist clinicians in identifying individuals at high risk of developing CKD.

Purpose: Molecular similarities have been reported between basal-like breast cancer (BLBC) and high-grade serous ovarian cancer (HGSOC). To date, there have been no prognostic biomarkers that can provide risk stratification and inform treatment decisions for both BLBC and HGSOC. In this study, we developed a molecular signature for risk stratification in BLBC and further validated this signature in HGSOC., Methods: RNA-seq data was downloaded from The Cancer Genome Atlas (TCGA) project for 190 BLBC and 314 HGSOC patients. Analyses of differentially expressed genes between recurrent vs. non-recurrent cases were performed using different bioinformatics methods. Gene Signature was established using weighted linear combination of gene expression levels. Their prognostic performance was evaluated using survival analysis based on progression-free interval (PFI) and disease-free interval (DFI)., Results: 63 genes were differentially expressed between 18 recurrent and 40 non-recurrent BLBC patients by two different methods. The recurrence index (RI) calculated from this 63-gene signature significantly stratified BLBC patients into two risk groups with 38 and 152 patients in the low-risk (RI-Low) and high-risk (RI-High) groups, respectively (p = 0.0004 and 0.0023 for PFI and DFI, respectively). Similar performance was obtained in the HGSOC cohort (p = 0.0131 and 0.004 for PFI and DFI, respectively). Multivariate Cox regression adjusting for age, grade, and stage showed that the 63-gene signature remained statistically significant in stratifying HGSOC patients (p = 0.0005)., Conclusion: A gene signature was identified to predict recurrence in BLBC and HGSOC patients. With further validation, this signature may provide an additional prognostic tool for clinicians to better manage BLBC, many of which are triple-negative and HGSOC patients who are currently difficult to treat.

Psoriasis is an inflammatory disease with both skin and joint manifestations. Focused biologics have been developed to target specific cytokines implicated in psoriasis and are becoming increasingly utilized. Recently, the advent of newer biologics, including IL-17, IL-12/IL-23, and IL-23 inhibitors, have garnered interest as promising treatments for psoriasis and other inflammatory conditions. Although IL-17 and IL-23 have been studied in the pathophysiology of psoriasis, they also play a central role in immunologic defenses, including those against fungi. Therefore, use of these interleukin inhibitors may theoretically impair the immune system against deep fungal infections. We reviewed the available literature investigating the risk for invasive fungal infections in patients treated with IL-17 and IL-23 inhibitors for psoriasis or other inflammatory conditions. Randomized controlled trials (RCTs), including extended trials and clinical trials, were reviewed, and we found that although there was a small number of patients who developed superficial candidiasis, there were no reports of invasive fungal disease. Although these results support the safety and the low risk for deep fungal infection with these biologics, caution is still warranted, as these medications are relatively new. Appropriate screening and management of fungal disease should still be practiced when utilizing these medications in the treatment of psoriasis and other inflammatory conditions.

Flexible manipulation of the carrier transport behaviors in two-dimensional materials determines their values of practical application in logic circuits. Here, we demonstrated the carrier-type manipulation in field-effect transistors (FETs) containing α-phase molybdenum ditelluride (MoTe 2 ) by a rapid thermal annealing (RTA) process in dry air for hole-dominated and electron-beam (EB) treatment for electron-dominated FETs. EB treatment induced a distinct shift of the transfer curve by around 135 V compared with that of the FET-processed RTA treatment, indicating that the carrier density of the EB-treated FET was enhanced by about 1 order of magnitude. X-ray photoelectron spectroscopy analysis revealed that the atomic ratio of Te decreased from 66.4 to 60.8% in the MoTe 2 channel after EB treatment. The Fermi level is pinned near the new energy level resulting from the Te vacancies produced by the EB process, leading to the electron-dominant effect of the MoTe 2 FET. The electron-dominated MoTe 2 FET showed excellent stability for more than 700 days. Thus, we not only realized the reversible modulation of carrier-type in layered MoTe 2 FETs but also demonstrated MoTe 2 channels with desirable performance, including long-term stability.

Introduction: Heterosexual infections have contributed to a high proportion of the HIV burden in Asia and Eastern Europe. Human mobility and non-local infections are important features in some cities/countries. An understanding of the determinants of the sustained growth of the heterosexual HIV epidemics would enable the potential impacts of treatment-based interventions to be assessed., Methods: We developed a compartmental model for heterosexual HIV transmissions, parameterized by clinical and surveillance data (1984-2014) in Hong Kong. HIV sequence data were included for examining genetic linkages and clustering pattern. We performed sensitivity analyses to evaluate effects of high-risk sexual partnership and proportions of non-locally acquired infections. Four hypothetical interventions (a) immediate treatment, (b) enhancement of retention in care, (c) HIV testing campaigns, and (d) test-and-treat strategy, were examined., Results: Data of 2174 patients (723 female and 1451 male) diagnosed with HIV between 1984 and 2012 in Hong Kong were collected for model parameterization. Among 1229 sequences of non-MSM (men who have sex with men) patients, 70% were isolates and 17% were either dyads or triads. In base-case scenario, the total estimated number of new infections in 2012-2023 would be 672 for male and 452 for female. Following 100% retention in care intervention, the total proportion of averted new infections in 2012-2023 would be 7% for male and 10% for female. HIV testing campaign in 2012 and 2017 followed by 100% immediate treatment strategy would avert 5% and 9% of male and female new infections, respectively. In the epidemic model, an increase of high-risk sexual partnership from 6% to 9% would increase the epidemic growth (annual number of newly diagnosed and newly infected cases) by about 10%. If no non-locally acquired infection occurred as from 2012, the epidemic growth would slump. To control the heterosexual epidemic, periodic HIV testing at 5-year intervals with immediate treatment would avert 5-13% of annual new infections in 2013-2023., Conclusions: Enhanced HIV testing with immediate treatment is most effective in controlling the heterosexual epidemic, the impacts of which might however be attenuated by any increase of non-locally acquired infection, assuming little variations of high risk partnership over time., Competing Interests: The authors have declared that no competing interests exist.

Motivation: Recent advances in single-cell sequencing (SCS) offer an unprecedented insight into tumor emergence and evolution. Principled approaches to tumor phylogeny reconstruction via SCS data are typically based on general computational methods for solving an integer linear program, or a constraint satisfaction program, which, although guaranteeing convergence to the most likely solution, are very slow. Others based on Monte Carlo Markov Chain or alternative heuristics not only offer no such guarantee, but also are not faster in practice. As a result, novel methods that can scale up to handle the size and noise characteristics of emerging SCS data are highly desirable to fully utilize this technology., Results: We introduce PhISCS-BnB (phylogeny inference using SCS via branch and bound), a branch and bound algorithm to compute the most likely perfect phylogeny on an input genotype matrix extracted from an SCS dataset. PhISCS-BnB not only offers an optimality guarantee, but is also 10-100 times faster than the best available methods on simulated tumor SCS data. We also applied PhISCS-BnB on a recently published large melanoma dataset derived from the sublineages of a cell line involving 20 clones with 2367 mutations, which returned the optimal tumor phylogeny in <4 h. The resulting phylogeny agrees with and extends the published results by providing a more detailed picture on the clonal evolution of the tumor., Availability and Implementation: https://github.com/algo-cancer/PhISCS-BnB., Supplementary Information: Supplementary data are available at Bioinformatics online., (Published by Oxford University Press 2020.)

Current cancer treatments are largely based on the genetic characterization of primary tumors and are ineffective for metastatic disease. Here we report that DNA methyltransferase 3B (DNMT3B) is induced at distant metastatic sites and mediates epigenetic reprogramming of metastatic tumor cells. Multiomics analysis and spontaneous metastatic mouse models revealed that DNMT3B alters multiple pathways including STAT3, NFκB, PI3K/Akt, β-catenin, and Notch signaling, which are critical for cancer cell survival, apoptosis, proliferation, invasion, and colonization. PGE2 and IL6 were identified as critical inflammatory mediators in DNMT3B induction. DNMT3B expression levels positively correlated with human metastatic progression. Targeting IL6 or COX-2 reduced DNMT3B induction and improved chemo or PD1 therapy. We propose a novel mechanism linking the metastatic microenvironment with epigenetic alterations that occur at distant sites. These results caution against the "Achilles heel" in cancer therapies based on primary tumor characterization and suggests targeting DNMT3B induction as new option for treating metastatic disease. SIGNIFICANCE: These findings reveal that DNMT3B epigenetically regulates multiple pro-oncogenic signaling pathways via the inflammatory microenvironment at distant sites, cautioning the clinical approach basing current therapies on genetic characterization of primary tumors., (©2020 American Association for Cancer Research.)

Exploitation of the oxidation behaviour in an environmentally sensitive semiconductor is significant to modulate its electronic properties and develop unique applications. Here, we demonstrate a native oxidation-inspired InSe field-effect transistor as an artificial synapse in device level that benefits from the boosted charge trapping under ambient conditions. A thin InO x layer is confirmed under the InSe channel, which can serve as an effective charge trapping layer for information storage. The dynamic characteristic measurement is further performed to reveal the corresponding uniform charge trapping and releasing process, which coincides with its surface-effect-governed carrier fluctuations. As a result, the oxide-decorated InSe device exhibits nonvolatile memory characteristics with flexible programming/erasing operations. Furthermore, an InSe-based artificial synapse is implemented to emulate the essential synaptic functions. The pattern recognition capability of the designed artificial neural network is believed to provide an excellent paradigm for ultra-sensitive van der Waals materials to develop electric-modulated neuromorphic computation architectures.

Background: Psoriasis is a chronic inflammatory skin disease that has been associated with a significantly higher risk of herpes zoster (HZ). Several newer biologics such as secukinumab, ixekizumab, and brodalumab inhibit IL-17 and have been highly effective for treatment of psoriasis. However, adverse events related to the immunosuppressive properties of these biologics have been observed. Methods: This review aims to synthesize and evaluate the literature investigating the risk of HZ in patients treated with IL-17 inhibitors, with a focus on psoriasis patients. We performed searches using the PubMED database with the following search terms: 'psoriasis,' 'herpes zoster,' 'secukinumab,' 'ixekizumab,' 'brodalumab,' 'IL-17,' 'anti-IL-17,' and 'safety.' Clinical trials, cohort studies, review articles, and meta-analyses were evaluated. Results: Studies did not detect a higher risk of HZ infections in psoriasis patients treated with IL-17 inhibitors when compared to those treated with placebo or other therapies. Studies of IL-17 inhibitors for other indications including psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and asthma yielded similar results. Conclusion: IL-17 inhibitors do not appear to increase risk of HZ. However, IL-17 inhibitors are relatively new medications, and further long-term data may be necessary to confirm this finding. Nevertheless, HZ vaccination should be considered on a case-bycase basis prior to initiating IL-17 therapy.

Peptidylarginine deiminases (PADI) catalyze posttranslational modification of many target proteins and have been suggested to play a role in carcinogenesis. Citrullination of histones by PADI4 was recently implicated in regulating embryonic stem and hematopoietic progenitor cells. Here, we investigated a possible role for PADI4 in regulating breast cancer stem cells. PADI4 activity limited the number of cancer stem cells (CSC) in multiple breast cancer models in vitro and in vivo . Mechanistically, PADI4 inhibition resulted in a widespread redistribution of histone H3, with increased accumulation around transcriptional start sites. Interestingly, epigenetic effects of PADI4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, PADI4 downregulated expression of master transcription factors of stemness, NANOG and OCT4, specifically in the cancer stem cell compartment, by reducing the transcriptionally activating H3R17me2a histone mark at those loci; this effect was not seen in the non-stem cells. A gene signature reflecting tumor cell-autonomous PADI4 inhibition was associated with poor outcome in human breast cancer datasets, consistent with a tumor-suppressive role for PADI4 in estrogen receptor-positive tumors. These results contrast with known tumor-promoting effects of PADI4 on the tumor stroma and suggest that the balance between opposing tumor cell-autonomous and stromal effects may determine net outcome. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells and provide insight into context-specific effects of PADI4 in epigenetic modulation. SIGNIFICANCE: These findings demonstrate a novel activity of the citrullinating enzyme PADI4 in suppressing breast cancer stem cells through epigenetic repression of stemness master transcription factors NANOG and OCT4., (©2020 American Association for Cancer Research.)

Background: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC., Methods: We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics., Results: Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51-0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L., Conclusions: Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.

Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy., Competing Interests: Conflict of Interest The authors describe no conflict of interests.

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

In this paper, we demonstrate a compact 20-W GaN internally matched power amplifier for 2.5 to 6 GHz jammer systems which uses a high dielectric constant substrate, single-layer capacitors, and shunt/series resistors for low-Q matching and low-frequency stabilization. A GaN high-electron-mobility transistor (HEMT) CGH60030D bare die from Wolfspeed was used as an active device, and input/output matching circuits were implemented on two different substrates using a thin-film process, relative dielectric constants of which were 9.8 and 40, respectively. A series resistor of 2.1 Ω was chosen to minimize the high-frequency loss and obtain a flat gain response. For the output matching circuit, double λ/4 shorted stubs were used to supply the drain current and reduce the output impedance variation of the transistor between the low-frequency and high-frequency regions, which also made wideband matching feasible. Single-layer capacitors effectively helped reduce the size of the matching circuit. The fabricated GaN internally matched power amplifier showed a linear gain of about 10.2 dB, and had an output power of 43.3-43.9 dBm (21.4-24.5 W), a power-added efficiency of 33.4%-49.7% and a power gain of 6.2-8.3 dB at the continuous-wave output power condition, from 2.5 to 6 GHz., Competing Interests: The authors declare no conflict of interest.

Purpose: TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored., Experimental Design: A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFβ antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms., Results: Heterogeneous responses to anti-TGFβ treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFβ antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFβ on the tumor cell. Applying transcriptomic signatures derived from treatment-naïve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor-negative disease are most likely to benefit from anti-TGFβ therapy., Conclusions: Contrary to dogma, tumor-suppressive responses to TGFβ are retained in some advanced metastatic tumors. Safe deployment of TGFβ antagonists in the clinic will require good predictive biomarkers., (©2019 American Association for Cancer Research.)

Molecular surveillance of infections is essential in monitoring their transmission in the population. In this study, newly diagnosed HIV patients' phylogenetic, clinical and behavioural data were integrated, and an information diffusion model was incorporated in analysing transmission dynamics. A genetic network was constructed from HIV sequences, from which transmission cascades were extracted. From the transmission cascades, CRF01&#95;AE had higher values of information diffusion metrics, including scale, speed and range, than that of B, signifying the distinct transmission patterns of two circulating subtypes in Hong Kong. Patients connected in the network, were more likely male, younger, of main circulating subtypes, to have acquired HIV infection locally, and a higher CD4 level at diagnosis. Genetic connections varied among men who have sex with men (MSM) who used different channels of sex networking and varied in their engagement in risk behaviours. MSM using recreational drugs for sex held positions of greater importance within the network. Significant differences in network metrics were observed among MSM as differentiated by their mobile apps usage patterns, evidencing the impact of social network on transmission networks. The applied model in the presence of consistently collected longitudinal data could enhance HIV molecular epidemiologic surveillance for informing future intervention planning.

Background: The prevalence of peanut allergy (PA) among children has increased significantly over the past decade. Even though the prevalence of PA in Singapore is considered low, peanut is the top trigger for food-induced anaphylaxis in Singaporean children., Objective: To describe the demographic characteristics and clinical features of children with PA., Methods: This is a 5-year retrospective review of children diagnosed with PA based on clinical history coupled with a positive skin prick test to peanut or positive oral food challenge results., Results: There were 269 patients (53.9% males) with a clinical diagnosis of PA. The median age at first allergic presentation for the PA group was 24 months old, with interquartile range of 13-39 months. The most common form of peanut introduced was roasted peanut. The rate of peanut anaphylaxis was 7.1%. Concomitant tree nut sensitization was found in 32.3% of this cohort, predominantly to cashew nut. Majority of them have a personal history of atopy - 75.8% with eczema, 63.6% with allergic rhinitis, and 19.7% with asthma., Conclusion: This is the first large review of peanut-allergic children in Singapore. Prospective population-based studies are needed to establish the true prevalence and risk factors associated with the development of this potentially life-threatening condition., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.

Background: The World Health Organization recommends continuation with the failing second-line regimen if third-line option is not available. We investigated treatment outcomes among people living with HIV in Asia who continued with failing second-line regimens compared with those who had treatment modifications after failure., Methods: Treatment modification was defined as a change of two antiretrovirals, a drug class change or treatment interruption (TI), all for >14 days. We assessed factors associated with CD4 changes and undetectable viral load (UVL <1,000 copies/ml) at 1 year after second-line failure using linear and logistic regression, respectively. Survival time was analysed using competing risk regression., Results: Of the 328 patients who failed second-line ART in our cohorts, 208 (63%) had a subsequent treatment modification. Compared with those who continued the failing regimen, the average CD4 cell increase was higher in patients who had a modification without TI (difference =77.5, 95% CI 35.3, 119.7) while no difference was observed among those with TI (difference =-5.3, 95% CI -67.3, 56.8). Compared with those who continued the failing regimen, the odds of achieving UVL was lower in patients with TI (OR=0.18, 95% CI 0.06, 0.60) and similar among those who had a modification without TI (OR=1.97, 95% CI 0.95, 4.10), with proportions of UVL 60%, 22% and 75%, respectively. Survival time was not affected by treatment modifications., Conclusions: CD4 cell improvements were observed in those who had treatment modification without TI compared with those on the failing regimen. When no other options are available, maintaining the same failing ART combination provided better VL control than interrupting treatment.

Background: This study investigated survival in people living with HIV being followed-up from 5 and 10 years after antiretroviral therapy (ART) initiation in a multi-country Asian cohort., Methods: We included patients in follow-up >5 years after ART initiation. Factors associated with mortality beyond 5 and 10 years on ART were analysed using competing risk regression with time-updated variables., Results: Of 13,495 patients retained after 5 years on ART, 279 subsequently died (0.56/100 person-years). Increased mortality was associated with age >50 years (sub-hazard ratio [sHR] 2.24, 95% CI 1.58, 3.15, compared with ≤40 years), HIV exposure through injecting drug use (sHR 2.17, 95% CI 1.32, 3.56), HIV viral load ≥1,000 copies/ml: sHR 1.52, 95% CI 1.05, 2.21, compared with <400), regimen (second-line regimen: sHR 2.11, 95% CI 1.52, 2.94, and third-line regimen: sHR 2.82, 95% CI 2.00, 3.98, compared with first-line regimen), HBV coinfection (sHR 2.23, 95% CI 1.49, 3.33), fasting plasma glucose ≥126 mg/dl (sHR 1.98, 95% CI 1.22, 3.21, compared with <100 mg/dl) and estimated glomerular filtration rate <60 ml/min/1.73 m 2 (sHR 2.57, 95% CI 1.56, 4.22). Decreased mortality was associated with transmission through male-to-male sexual contact (sHR 0.44, 95% CI 0.22, 0.88, compared with heterosexual transmission) and higher CD4 + T-cell count (200-349 cells/µl: sHR 0.27, 95% CI 0.20, 0.38, 350-499 cells/µl: sHR 0.10, 95% CI 0.07, 0.16 and ≥500 cells/µl: sHR 0.09, 95% CI 0.06, 0.13, compared with <200 cells/µl). Results after 10 years were similar, but most associations were weaker due to limited power., Conclusions: Next to preventing ART failure, HIV programmes should carefully monitor and treat comorbidities, including hepatitis, kidney disease and diabetes, to optimize survival after long-term ART exposure.

Background: Comprehensive treatment and clinical management are central to improving outcomes for people living with HIV (PLHIV). We explored trends in HIV clinical care, treatment outcomes, and chronic kidney disease (CKD) and diabetes monitoring., Methods: We included patients ≥18 years in care at ten clinical sites in eight Asian countries. Proportions of patients on antiretroviral therapy (ART), with annual viral load, and with viral load suppression (VLS; <1,000 copies/ml) were estimated by year for 2011-2016, stratified by country income level (lower-middle income [LMIC] and high-income countries [HIC]). Among those on ART in 2016 we evaluated factors associated with annual CKD and diabetes monitoring., Results: Among 31,346 patients (67% male), the proportions of patients on ART (median ART initiation year 2011, IQR 2007-2013), with annual viral load and VLS had substantially increased by 2016 (to 94%, 42% and 92%, respectively, in LMIC and 95%, 97% and 93%, respectively, in HIC) with the larger increases over time seen in LMIC. Among those on ART in 2016, monitoring proportions in LMIC were 53% for CKD and 26% for diabetes compared with 83% and 59%, respectively, in HIC. Overall, a decreased odds of monitoring was observed for male gender, heterosexual HIV exposure, no viral load and LMIC. Diabetes monitoring was also decreased in those with viral failure., Conclusions: Our findings highlight suboptimal monitoring of viral load, CKD and diabetes in PLHIV in Asia. There is a need for affordable and scalable monitoring options to improve the joint care for HIV and non-communicable diseases.

Importance: National Comprehensive Cancer Network guidelines for melanoma have consistently recommended wide local excision as the standard of care since their inception. Although surgery with more comprehensive margin assessment (eg, Mohs surgery) has been advocated for certain subsets of melanoma, how often these techniques are used in clinical practice is uncertain., Objective: To examine trends in the use of comprehensive margin assessment surgery for melanoma by tracking claims data for Mohs surgery., Design, Setting, and Participants: This national cross-sectional analysis examined claims data from the Optum Clinformatics Data Mart, a nationally representative database. The study cohort consisted of 79 108 patients undergoing surgical excision for melanoma from January 1, 2001, through December 31, 2016. Data were analyzed from January 1, 2001, through December 31, 2016., Main Outcomes and Measures: The primary outcome was the likelihood of a melanoma being treated with Mohs surgery over time, evaluated by multivariable logistic regression and expressed as the odds of treatment per additional calendar year., Results: Among 79 108 patients with melanoma (median age, 63 years [interquartile range {IQR}, 51-73]; 47 407 men [59.9%]), 75 047 were treated with conventional excision (median age, 62 years [IQR, 50-73 years]; 44 786 men [59.7%]) and 4061 with Mohs surgery (median age, 67 years [IQR, 56-76 years]; 2621 men [64.5%]). Mohs surgery was used in 5.1% of all surgical cases, with the rate of Mohs surgery increasing 304% from 2.6% in 2001 to 7.9% in 2016. Odds of receiving Mohs surgery for melanoma increased significantly in more recent calendar years (odds ratio [OR], 1.02 per calendar year; 95% CI, 1.01-1.03; P < .001). Immunohistochemistry (IHC) use was only coded with Mohs surgery in 1087 cases (26.8%), and the odds of receiving Mohs surgery with IHC increased in more recent calendar years (OR, 1.13 per calendar year; 95% CI, 1.10-1.15; P < .001). Use of Mohs surgery and Mohs surgery with IHC for melanoma differed widely across geographic census divisions with greater than 3-fold variation between the regions with highest and lowest use in every period (eg, for 2013 through 2016, the East South Central region used Mohs surgery in 8.8% of melanoma excisions compared with 2.6 in the New England region)., Conclusions and Relevance: Despite stable guidelines for melanoma surgery, the results of this study suggest that surgical practices for melanoma are evolving. Wide variations in surgical practice patterns for melanoma are present in the United States. This study's findings suggest that the effect of variations in surgical techniques on outcomes requires scrutiny and further study.

Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines., (© 2019 Wiley Periodicals, Inc.)

Importance: There is a need for better understanding of the comparative safety of systemic medications used in the treatment of psoriasis., Objective: To compare the risk of serious infection associated with biologic and nonbiologic systemic medications in patients with psoriasis., Design, Setting, and Participants: An observational cohort study was conducted using medical and outpatient pharmacy claims from 2 large US health insurance claims databases from January 1, 2003, through September 30, 2015. We included patients with a diagnosis of psoriasis who were new users of systemic medications for psoriasis., Exposures: Prescription claims for acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, or ustekinumab., Main Outcomes and Measures: The primary outcome was serious infection, defined by inpatient discharge diagnosis International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Cox proportional hazards regression was used to compare rates of serious infection for each exposure (acitretin, adalimumab, apremilast, etanercept, infliximab, and ustekinumab) with the referent group (methotrexate). We used pairwise 1:1 propensity score (PS) matching to adjust for potential confounders, which were assessed during a 180-day baseline period prior to study drug initiation. Results from the 2 databases were pooled via fixed-effects analysis., Results: The databases included 31 595 patients in the Optum Clinformatics Data Mart and 76 112 patients in Truven MarketScan who were new users of acitretin, adalimumab, apremilast, etanercept, infliximab, methotrexate, and ustekinumab. Users of acitretin, apremilast, infliximab, and methotrexate were older and had higher baseline comorbidity scores than subcutaneous biologic users (adalimumab, etanercept, and ustekinumab). The pooled PS-matched analysis yielded a decreased rate of overall serious infection in users of apremilast (hazard ratio [HR], 0.50; 95% CI, 0.26-0.94), etanercept (HR, 0.75; 95% CI, 0.61-0.93), and ustekinumab (HR, 0.65; 95% CI, 0.47-0.89) compared with methotrexate. We did not find a different rate of overall serious infection among users of acitretin, adalimumab, and infliximab compared with methotrexate. Subanalysis by type of serious infection showed a significantly increased risk of cellulitis among users of acitretin compared with methotrexate (PS-adjusted HR, 1.76; 95% CI, 1.11-2.80)., Conclusions and Relevance: Among patients with psoriasis treated with systemic medications in 2 large US claims databases, new users of apremilast, etanercept, and ustekinumab had a decreased rate of serious infection compared with methotrexate.

Epigenetic information is characterized by its stable transmission during mitotic cell divisions and plasticity during development and differentiation. This duality is in contrast to genetic information, which is stable and identical in all cells in an organism with exception of immunoglobulin gene rearrangements in lymphocytes and somatic mutations in cancer cells. Allele-specific analysis of gene expression and epigenetic modifications provides a unique approach to studying epigenetic regulation in normal and cancer cells. Extension of Knudson's two-hits theory to include epigenetic alteration as a means to inactivate tumor suppressor genes provides better understanding of how genetic mutations and epigenetic alterations jointly contribute to cancer development. High-throughput technology has greatly accelerated cancer discovery. Large initiatives such as TCGA have shown that epigenetic components are frequent targets of mutations in cancer and these discoveries provide new insights into understanding cancer etiology and generate new opportunities for cancer therapeutics.

Objectives: With earlier antiretroviral therapy (ART) initiation, time spent in HIV care is expected to increase. We aimed to investigate loss to follow-up (LTFU) in Asian patients who remained in care 5 years after ART initiation., Methods: Long-term LTFU was defined as LTFU occurring after 5 years on ART. LTFU was defined as (1) patients not seen in the previous 12 months; and (2) patients not seen in the previous 6 months. Factors associated with LTFU were analysed using competing risk regression., Results: Under the 12-month definition, the LTFU rate was 2.0 per 100 person-years (PY) [95% confidence interval (CI) 1.8-2.2 among 4889 patients included in the study. LTFU was associated with age > 50 years [sub-hazard ratio (SHR) 1.64; 95% CI 1.17-2.31] compared with 31-40 years, viral load ≥ 1000 copies/mL (SHR 1.86; 95% CI 1.16-2.97) compared with viral load < 1000 copies/mL, and hepatitis C coinfection (SHR 1.48; 95% CI 1.06-2.05). LTFU was less likely to occur in females, in individuals with higher CD4 counts, in those with self-reported adherence ≥ 95%, and in those living in high-income countries. The 6-month LTFU definition produced an incidence rate of 3.2 per 100 PY (95% CI 2.9-3.4 and had similar associations but with greater risks of LTFU for ART initiation in later years (2006-2009: SHR 2.38; 95% CI 1.93-2.94; and 2010-2011: SHR 4.26; 95% CI 3.17-5.73) compared with 2003-2005., Conclusions: The long-term LTFU rate in our cohort was low, with older age being associated with LTFU. The increased risk of LTFU with later years of ART initiation in the 6-month analysis, but not the 12-month analysis, implies that there was a possible move towards longer HIV clinic scheduling in Asia., (© 2019 British HIV Association.)

Validating digital pathology as substitute for conventional microscopy in diagnosis remains a priority to assure effectiveness. Intermodality concordance studies typically focus on achieving the same diagnosis by digital display of whole slide images and conventional microscopy. Assessment of discrete histological features in whole slide images, such as mitotic figures, has not been thoroughly evaluated in diagnostic practice. To further gauge the interchangeability of conventional microscopy with digital display for primary diagnosis, 12 pathologists examined 113 canine naturally occurring mucosal melanomas exhibiting a wide range of mitotic activity. Design reflected diverse diagnostic settings and investigated independent location, interpretation, and enumeration of mitotic figures. Intermodality agreement was assessed employing conventional microscopy (CM40×), and whole slide image specimens scanned at 20× (WSI20×) and at 40× (WSI40×) objective magnifications. An aggregate 1647 mitotic figure count observations were available from conventional microscopy and whole slide images for comparison. The intraobserver concordance rate of paired observations was 0.785 to 0.801; interobserver rate was 0.784 to 0.794. Correlation coefficients between the 2 digital modes, and as compared to conventional microscopy, were similar and suggest noninferiority among modalities, including whole slide image acquired at lower 20× resolution. As mitotic figure counts serve for prognostic grading of several tumor types, including melanoma, 6 of 8 pathologists retrospectively predicted survival prognosis using whole slide images, compared to 9 of 10 by conventional microscopy, a first evaluation of whole slide image for mitotic figure prognostic grading. This study demonstrated agreement of replicate reads obtained across conventional microscopy and whole slide images. Hence, quantifying mitotic figures served as surrogate histological feature with which to further credential the interchangeability of whole slide images for primary diagnosis., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 (P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes contained in two clusters were particularly affected: the first cluster on cytoband 13q13 contained 7 highly up-regulated genes (NBEA, MAB21L1, DCLK1, SOHLH2, CCDC169, SPG20 and CCNA1, P = .0003) in all clones. A second cluster was located on 13q32.1 and contained five upregulated genes (ABCC4, CLDN10, DZIP1, DNAJC3 and UGGT2, P = .003). One gene, RASL11A, localized on chromosome band 13q12.2, escaped the copy number-induced overexpression and was reproducibly and significantly down-regulated on the mRNA and protein level (P = .0001, FDR = 0.002). RASL11A expression levels were also lower in primary colorectal tumors as compared to matched normal mucosa (P = .0001, FDR = 0.0001. Overexpression of RASL11A increases cell proliferation and anchorage independent growth while decreasing cell migration in +13 clones. In summary, we observed a strict correlation of genomic copy number and resident gene expression levels, and aneuploidy dependent consistent genome-wide transcriptional deregulation., (Copyright © 2019. Published by Elsevier Inc.)

Patient-centered care in dermatologic surgery emphasizes addressing the preferences, values, and concerns of the surgical patient in an effort to improve the overall experience. Impediments affecting the delivery of Mohs micrographic surgical treatment of skin cancers are present throughout the perioperative period. Defining actionable strategies to improve outcomes can be challenging due to sparse literature and minimal high-quality scientific studies. This review focuses on the current evidence supporting practical recommendations in each surgical setting to improve the patient experience and increase visit satisfaction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Accumulating evidence indicates that there is an increased risk of cardiovascular disease among patients with psoriatic disease. Although an emerging concern that the risk of atrial fibrillation (AF) may also be higher in this patient population adds to the growing support of initiating early interventions to control systemic inflammation, evidence on the comparative cardiovascular safety of current biologic treatments remains limited., Objective: To evaluate the risk of AF and major adverse cardiovascular events (MACE) associated with use of ustekinumab vs tumor necrosis factor inhibitors (TNFi) in patients with psoriasis or psoriatic arthritis., Design, Setting, and Participants: This cohort study included data from a nationwide sample of 78 162 commercially insured patients in 2 US commercial insurance databases (Optum and MarketScan) from September 25, 2009, through September 30, 2015. Patients were included if they were 18 years or older, had psoriasis or psoriatic arthritis, and initiated ustekinumab or a TNFi therapy. Exclusion criteria included history of AF or receipt of antiarrhythmic or anticoagulant therapy during the baseline period., Exposures: Initiation of ustekinumab vs TNFi therapy., Main Outcomes and Measures: Incident AF and MACE, including myocardial infarction, stroke, or coronary revascularization., Results: A total of 60 028 patients with psoriasis or psoriatic arthritis (9071 ustekinumab initiators and 50 957 TNFi initiators) were included in the analyses. The mean (SD) age was 46 (13) years in Optum and 47 (13) in MarketScan, and 29 495 (49.1%) were male. Overall crude incidence rates (reported per 1000 person-years) for AF were 5.0 (95% CI, 3.8-6.5) for ustekinumab initiators and 4.7 (95% CI, 4.2-5.2) for TNFi initiators, and for MACE were 6.2 (95% CI, 4.9-7.8) for ustekinumab initiators and 6.1 (95% CI, 5.5-6.7) for TNFi initiators. The combined adjusted hazard ratio for incident AF among ustekinumab initiators was 1.08 (95% CI, 0.76-1.54) and for MACE among ustekinumab initiators was 1.10 (95% CI, 0.80-1.52) compared with TNFi initiators., Conclusions and Relevance: No substantially different risk of incident AF or MACE after initiation of ustekinumab vs TNFi was observed in this study. This information may be helpful when weighing the risks and benefits of various systemic treatment strategies for psoriatic disease.

Breast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity., Competing Interests: The authors have declared that no competing interests exist.

Background: HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known., Methods: Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment., Results: Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments., Conclusions: Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.

Background: Determining mitotic index by counting mitotic figures (MFs) microscopically from tumor areas with most abundant MF (hotspots [HS]) produces a prognostically useful tumor grading biomarker. However, interobserver concordance identifying MF and HS can be poorly reproducible. Immunolabeling MF, coupled with computer-automated counting by image analysis, can improve reproducibility. A computational system for obtaining MF values across digitized whole-slide images (WSIs) was sought that would minimize impact of artifacts, generate values clinically relatable to counting ten high-power microscopic fields of view typical in conventional microscopy, and that would reproducibly map HS topography., Materials and Methods: Relatively low-resolution WSI scans (0.50 μm/pixel) were imported in grid-tile format for feature-based MF segmentation, from naturally occurring canine melanomas providing a wide range of proliferative activity. MF feature extraction conformed to anti-phospho-histone H3-immunolabeled mitotic (M) phase cells. Computer vision image processing was established to subtract key artifacts, obtain MF counts, and employ rotationally invariant feature extraction to map MF topography., Results: The automated topometric HS (TMHS) algorithm identified mitotic HS and mapped select tissue tiles with greatest MF counts back onto WSI thumbnail images to plot HS topographically. Influence of dye, pigment, and extraneous structure artifacts was minimized. TMHS diagnostic decision support included image overlay graphics of HS topography, as well as a spreadsheet and plot of tile-based MF count values. TMHS performance was validated examining both mitotic HS counting and mapping functions. Significantly correlated TMHS MF mapping and metrics were demonstrated using repeat analysis with WSI in different orientation ( R 2 = 0.9916) and by agreement with a pathologist ( R 2 = 0.8605) as well as through assessment of counting function using an independently tuned object counting algorithm (OCA) ( R 2 = 0.9482). Limits of agreement analysis support method interchangeability. MF counts obtained led to accurate patient survival prediction in all ( n = 30) except one case. By contrast, more variable performance was documented when several pathologists examined similar cases using microscopy (pair-wise correlations, rho range = 0.7597-0.9286)., Conclusions: Automated TMHS MF segmentation and feature engineering performance were interchangeable with both observer and OCA in digital mode. Moreover, enhanced HS location accuracy and superior method reproducibility were achieved using the automated TMHS algorithm compared to the current practice employing clinical microscopy., Competing Interests: There are no conflicts of interest.

Introduction: Multiple comorbidities among HIV-positive individuals may increase the potential for polypharmacy causing drug-to-drug interactions and older individuals with comorbidities, particularly those with cognitive impairment, may have difficulty in adhering to complex medications. However, the effects of age-associated comorbidities on the treatment outcomes of combination antiretroviral therapy (cART) are not well known. In this study, we investigated the effects of age-associated comorbidities on therapeutic outcomes of cART in HIV-positive adults in Asian countries., Methods: Patients enrolled in the TREAT Asia HIV Observational Database cohort and on cART for more than six months were analysed. Comorbidities included hypertension, diabetes, dyslipidaemia and impaired renal function. Treatment outcomes of patients ≥50 years of age with comorbidities were compared with those <50 years and those ≥50 years without comorbidities. We analysed 5411 patients with virological failure and 5621 with immunologic failure. Our failure outcomes were defined to be in-line with the World Health Organization 2016 guidelines. Cox regression analysis was used to analyse time to first virological and immunological failure., Results: The incidence of virologic failure was 7.72/100 person-years. Virological failure was less likely in patients with better adherence and higher CD4 count at cART initiation. Those acquiring HIV through intravenous drug use were more likely to have virological failure compared to those infected through heterosexual contact. On univariate analysis, patients aged <50 years without comorbidities were more likely to experience virological failure than those aged ≥50 years with comorbidities (hazard ratio 1.75, 95% confidence interval (CI) 1.31 to 2.33, p < 0.001). However, the multivariate model showed that age-related comorbidities were not significant factors for virological failure (hazard ratio 1.31, 95% CI 0.98 to 1.74, p = 0.07). There were 391 immunological failures, with an incidence of 2.75/100 person-years. On multivariate analysis, those aged <50 years without comorbidities (p = 0.025) and age <50 years with comorbidities (p = 0.001) were less likely to develop immunological failure compared to those aged ≥50 years with comorbidities., Conclusions: In our Asia regional cohort, age-associated comorbidities did not affect virologic outcomes of cART. Among those with comorbidities, patients <50 years old showed a better CD4 response., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: Comorbidities including diabetes mellitus (DM) among people living with HIV (PLHIV) are of increasing clinical concerns in combination antiretroviral therapy (cART) era. We aimed to determine the incidence and risk factors of new-onset DM among PLHIV in Asian settings., Methods: PLHIV from a regional observational cohort without DM prior to antiretroviral therapy (ART) initiation were included in the analysis. DM was defined as having a fasting blood glucose ≥126 mg/dL, glycated haemoglobin ≥6.5%, a two-hour plasma glucose ≥200 mg/dL, or a random plasma glucose ≥200 mg/dL. A Cox regression model, stratified by site, was used to identify risk factors associated with DM., Results and Discussion: Of the 1927 participants included, 127 were diagnosed with DM after ART initiation. Median follow-up time from ART initiation to DM diagnosis was 5.9 years (interquartile range (IQR): 2.8 to 8.9 years). The crude incidence rate of DM was 1.08 per 100 person-years (100 PYS), 95% confidence interval (CI) (0.9 to 1.3). In the multivariate analysis, later years of follow-up (2011 to 2013: HR = 2.34, 95% CI 1.14 to 4.79, p = 0.02; and 2014 to 2017: HR = 7.20, 95% CI 3.27 to 15.87, p < 0.001) compared to <2010, older age (41 to 50 years: HR = 2.46, 95% CI 1.39 to 4.36, p  = 0.002; and >50 years: HR = 4.19, 95% CI 2.12 to 8.28, p < 0.001) compared to <30 years, body mass index (BMI) >30 kg/m 2 (HR = 4.3, 95% CI 1.53 to 12.09, p = 0.006) compared to BMI <18.5 kg/m 2 , and high blood pressure (HR = 2.05, 95% CI 1.16 to 3.63, p = 0.013) compared to those without high blood pressure, were associated with developing DM. The hazard was reduced for females (HR = 0.47, 95% CI 0.28 to 0.80, p = 0.006)., Conclusions: Type 2 DM in HIV-infected Asians was associated with later years of follow-up, high blood pressure, obesity and older age. This highlights the importance of monitoring and routine screening for non-communicable diseases including DM as PLHIV age., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Nonadherence to systemic treatments for psoriasis leads to treatment failure and increased health care utilization., Objective: Examine drug utilization patterns and adherence of new users of systemic medications for psoriasis., Methods: We conducted a retrospective, comparative cohort study using a large US health insurance claims database including psoriasis patients who were new users of acitretin, adalimumab, etanercept, methotrexate, or ustekinumab. Adherence was measured by using proportion of days covered dichotomized as adherent (≥0.80) or nonadherent (<0.80). Odds ratios (ORs) and 95% confidence intervals (CIs) comparing adherence to each exposure (acitretin, adalimumab, etanercept, or ustekinumab) to the referent (methotrexate) were estimated via logistic regression, with pairwise 1:1 propensity score matching to adjust for potential confounders., Results: In total, 22,742 patients were new users of systemic medications. Among these patients, adherence to adalimumab (OR 2.24, 95% CI 2.05-2.45); etanercept (OR 1.77, 95% CI 1.63-1.92); and ustekinumab (OR 2.54, 95% CI 2.24-2.87) was greater and acitretin (OR 0.57, 95% CI 0.50-0.63) lower compared with methotrexate., Limitations: Unable to evaluate reasons for discontinuation., Conclusion: We report greater adherence to biologics than methotrexate in new users. Further research is needed to understand overall low adherence to systemic medications for psoriasis., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Missed clinic visits can lead to poorer treatment outcomes in HIV-infected patients. Suboptimal antiretroviral therapy (ART) adherence has been linked to subsequent missed visits. Knowing the determinants of missed visits in Asian patients will allow for appropriate counselling and intervention strategies to ensure continuous engagement in care. A missed visit was defined as having no assessments within six months. Repeated measures logistic regression was used to analyse factors associated with missed visits. A total of 7100 patients were included from 12 countries in Asia with 2676 (37.7%) having at least one missed visit. Patients with early suboptimal self-reported adherence <95% were more likely to have a missed visit compared to those with adherence ≥95% (OR = 2.55, 95% CI(1.81-3.61)). Other factors associated with having a missed visit were homosexual (OR = 1.45, 95%CI(1.27-1.66)) and other modes of HIV exposure (OR = 1.48, 95%CI(1.27-1.74)) compared to heterosexual exposure; using PI-based (OR = 1.33, 95%CI(1.15-1.53) and other ART combinations (OR = 1.79, 95%CI(1.39-2.32)) compared to NRTI+NNRTI combinations; and being hepatitis C co-infected (OR = 1.27, 95%CI(1.06-1.52)). Patients aged >30 years (31-40 years OR = 0.81, 95%CI(0.73-0.89); 41-50 years OR = 0.73, 95%CI(0.64-0.83); and >50 years OR = 0.77, 95%CI(0.64-0.93)); female sex (OR = 0.81, 95%CI(0.72-0.90)); and being from upper middle (OR = 0.78, 95%CI(0.70-0.80)) or high-income countries (OR = 0.42, 95%CI(0.35-0.51)), were less likely to have missed visits. Almost 40% of our patients had a missed clinic visit. Early ART adherence was an indicator of subsequent clinic visits. Intensive counselling and adherence support should be provided at ART initiation in order to optimise long-term clinic attendance and maximise treatment outcomes.

Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression., (© 2018 Yu et al.; Published by Cold Spring Harbor Laboratory Press.)

In this paper, we present a Ku-band 50 W internally-matched power amplifier that asymmetrically combines the power transistor cells of the GaN high electron mobility transistor (HEMT) (CGHV1J070D) from Wolfspeed. The amplifier is designed using a large-signal transistor cell model in the foundry process, and asymmetric power combining, which consists of a slit pattern, oblique wire bonding and an asymmetric T-junction, is applied to obtain the amplitude/phase balance of the combined signals at the transistor cell combining position. Input and output matching circuits are implemented using a thin film process on a titanate substrate and an alumina substrate with the relative dielectric constants of 40 and 9.8, respectively. The pulsed measurement of a 330 μs pulse period and 6% duty cycle shows the maximum saturated output power of 57 to 66 W, drain efficiency of 40.3 to 46.7%, and power gain of 5.3 to 6.0 dB at power saturation from 16.2 to 16.8 GHz.

Numerous factors contribute to the onset and exacerbation of psoriasis. Genetic risk factors include HLA-Cw6 and mutations in the caspase recruitment domain family member 14 gene, CARD14 . Environmental risk factors, including infectious diseases, medications, and lifestyle, also have been implicated. It is important for clinicians to be aware of these risk factors and triggers because they might provide insight into the pathogenesis of psoriasis as well as help patients understand more about their disease.

Background: Medication nonadherence is a major public health problem. Identification of patients who are likely to be and not be adherent can guide targeted interventions and improve the design of comparative-effectiveness studies., Objective: To evaluate multiple measures of patient previous medication adherence in light of predicting future statin adherence in a large U.S. administrative claims database., Methods: We identified a cohort of patients newly initiating statins and measured their previous adherence to other chronic preventive medications during a 365-day baseline period, using metrics such as proportion of days covered (PDC), lack of second fills, and number of dispensations. We measured adherence to statins during the year after initiation, defining high adherence as PDC ≥ 80%. We built logistic regression models from different combinations of baseline variables and previous adherence measures to predict high adherence in a random 50% sample and tested their discrimination using concordance statistics (c-statistics) in the other 50%. We also assessed the association between previous adherence and subsequent statin high adherence by fitting a modified Poisson model from all relevant covariates plus previous mean PDC categorized as < 25%, 25%-79%, and ≥ 80%., Results: Among 89,490 statin initiators identified, a prediction model including only demographic variables had a c-statistic of 0.578 (95% CI = 0.573-0.584). A model combining information on patient comorbidities, health care services utilization, and medication use resulted in a c-statistic of 0.665 (95% CI = 0.659-0.670). Models with each of the previous medication adherence measures as the only explanatory variable yielded c-statistics ranging between 0.533 (95% CI = 0.529-0.537) for lack of second fill and 0.666 (95% CI = 0.661-0.671) for maximum PDC. Adding mean PDC to the combined model yielded a c-statistic of 0.695 (95% CI = 0.690-0.700). Given a sensitivity of 75%, the predictor improved the specificity from 47.7% to 53.6%. Patients with previous mean PDC < 25% were half as likely to show high adherence to statins compared with those with previous mean PDC ≥ 80% (risk ratio = 0.49, 95% CI = 0.46-0.50)., Conclusions: Including measures of previous medication adherence yields better prediction of future statin adherence than usual baseline clinical measures that are typically used in claims-based studies., Disclosures: This study was funded by the Patient-Centered Outcomes Research Institute (ME-1309-06274). Kumamaru, Kohsaka, and Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo, which is a social collaboration department supported by National Clinical Database. The department was formerly supported by endowments from Johnson & Johnson K.K., Nipro, Teijin Pharma, Kaketsuken K.K., St. Jude Medical Japan, Novartis Pharma K.K., Taiho Pharmaceutical, W. L. Gore & Associates, Olympus Corporation, and Chugai Pharmaceutical. Gagne has received grants from Novartis Pharmaceuticals and Eli Lilly and Company to the Brigham and Women's Hospital for unrelated work. He is a consultant to Aetion, a software company, and to Optum. Choudhry has received grants from the National Heart, Lung, and Blood Institute, PhRMA Foundation, Merck, Sanofi, AstraZeneca, CVS, and MediSafe. Schneeweiss is consultant to WHISCON and Aetion, a software manufacturer of which he also owns equity. He is principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, and Boehringer Ingelheim unrelated to the topic of this study. He does not receive personal fees from biopharmaceutical companies. No potential conflict of interest was reported by the other authors.

Purpose: Renal disease is common among people living with human immunodeficiency virus (HIV). However, there is limited information on the incidence and risk factors associated with renal dysfunction among this population in Asia., Methods: We used data from the TREAT Asia HIV Observational Database. Patients were included if they started antiretroviral therapy during or after 2003, had a serum creatinine measurement at antiretroviral therapy initiation (baseline), and had at least 2 follow-up creatinine measurements taken ≥3 months apart. Patients with a baseline estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m 2 were excluded. Chronic kidney disease was defined as 2 consecutive eGFR values ≤60 mL/min/1.73 m 2 taken ≥3 months apart. Generalized estimating equations were used to identify factors associated with eGFR change. Competing risk regression adjusted for study site, age and sex, and cumulative incidence plots were used to evaluate factors associated with chronic kidney disease (CKD)., Results: Of 2547 patients eligible for this analysis, tenofovir was being used by 703 (27.6%) at baseline. Tenofovir use, high baseline eGFR, advanced HIV disease stage, and low nadir CD4 were associated with a decrease in eGFR during follow-up. Chronic kidney disease occurred at a rate of 3.4 per 1000 patient/years. Factors associated with CKD were tenofovir use, old age, low baseline eGFR, low nadir CD4, and protease inhibitor use., Conclusions: There is an urgent need to enhance renal monitoring and management capacity among at-risk groups in Asia and improve access to less nephrotoxic antiretrovirals., (© 2018 John Wiley & Sons, Ltd.)

Introduction: Data are limited regarding risk factors for mortality among patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) in areas with low HIV prevalence and intermediate TB burden, such as the Western Pacific region. This study aimed to assess such risk factors in Hong Kong, which has an intermediate TB burden and low HIV prevalence., Methods: We conducted a retrospective cohort analysis of adult patients reported to the Hong Kong TB-HIV Registry between 2006 and 2015. Baseline characteristics were compared with Kaplan-Meier estimates. Cox proportional hazards regression modelling was used to identify factors associated with mortality., Results: Of 299 patients studied, 21 (7.0%) died within 12 months of anti-TB treatment (median [interquartile range], 7.5 [3.8-10] months). The median age of death was 54 (interquartile range, 40.5-75.0) years. The cause of death was TB in five and unrelated to TB in the remaining 16. Cox proportional hazards regression showed that older age (adjusted hazard ratio=4.5; 95% confidence interval [CI]=1.4-14.9), history of drug addiction (4.6; 95% CI=1.6-13.0), and low baseline CD4 cell count of <50/μL (2.9; 95% CI=1.1-7.7) were independent risk factors for death within 12 months., Conclusion: This study complements previous studies by providing information regarding risk factors associated with mortality among patients with HIV-associated TB in areas with intermediate TB burden and low HIV prevalence. The results from our study may guide targeted measures to improve survival in other areas with intermediate TB burden and low HIV prevalence, such as the Western Pacific region.

Pre-exposure prophylaxis (PrEP) targeting high-risk men who have sex with men (MSM) has been shown to be a cost-effective HIV control measure. However, the approach could be a challenge in low HIV incidence places with a low proportion of high-risk MSM. To examine the impact of PrEP in such setting in Asia, we developed an epidemic model and conducted cost-effectiveness analysis using empirical multicentre clinical and HIV sequence data from HIV-infected MSM in Hong Kong, in conjunction with behavioural data of local MSM. Without PrEP, the HIV incidence (per 100 person-years) would increase from 1.1 to 1.6 between 2011 and 2021. PrEP could avert 3-63% of total new infections in a five-year period (2017-2021), the variability of which depends on the implementation strategies and combination with test-and-treat. However, under current market drug price in 2016, the incremental cost per quality-adjusted life-year gained (QALYG) of PrEP (USD1583136/QALYG) is almost 3 times higher than test-and-treat intervention alone (USD396874/QALYG). Assuming 93% fall of PrEP drug price and in combination with test-and-treat, putting 30% of MSM on non-targeting PrEP would be more feasible, cost-effective (USD268915/QALYG), and could avert more new infections (40%). PrEP could contribute to HIV epidemic control in a low incidence place.