Cd4+ T Cell Recovery And Cerebrospinal Fluid Escape After Antiretroviral Therapy Initiation In Acute Hiv-1 Infection

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to \u3e500 cells/mm3 and up to 10% have quantifiable HIV RNA in cerebrospinal fluid (CSF), termed CSF escape, despite plasma viral suppression \u3c 50 copies/mL. Previous studies have shown that ART initiation in the earliest stage of identifiable infection, acute HIV infection (prior to antibody seroconversion), may limit viral reservoir establishment and systemic immune activation and may improve clinical outcomes. We investigated the frequency, associations, and outcomes of suboptimal CD4 recovery (Project 1) and CSF escape (Project 2) after ART started during acute HIV infection (AHI). Methods: Thai participants with laboratory-confirmed diagnosis of AHI (Fiebig stages I to V) were started immediately on ART and followed longitudinally with blood sampling, neuropsychological and neurobehavioral testing, and optional lumbar puncture. For Project 1, participants with ≥48 weeks of documented HIV RNA \u3c50 copies/mL were stratified by CD4 count at latest study visit to suboptimal recovery (SR; CD4\u3c350 cells/mm3), intermediate recovery (IR; 350≤CD4\u3c500), and complete recovery (CR; CD4≥500). To assess determinants of CD4 recovery, clinical and laboratory parameters were evaluated at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks. For Project 2, participants who underwent blood sampling and optional CSF sampling at weeks 24 and 96 were assessed for CSF escape. HIV RNA was quantified using Roche Amplicor and COBAS TaqMan assays with a lower limit of quantitation of 20-50 copies/mL in plasma and 80 copies/mL in CSF. Participants with quantifiable CSF HIV RNA greater than that in plasma during ART were identified as cases of CSF escape. Results, Project 1: Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60-420) weeks of ART initiated at median 19 days (range 1-62) post-exposure, 3.6% (n=11) had SR, 14.5% (n=44) had IR, and 81.9% (n=249) had CR. Degree of CD4 recovery occurred early following ART. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Pre-ART CD4 count in SR compared to CR participants was 265 vs 411 cells/mm3 (p=0.002). Following ART, the CD8+ T cell count (p=0.001) and CD4/CD8 ratio (p=0.047) were lower in SR compared to CR participants. Compared to the CR group at week 96, the combined SR and IR groups had higher sCD14 (p=0.008) and lower IL-6 (p=0.04) in plasma, without differences in neuropsychological or psychiatric indices. After adjusting for duration of ART, baseline HIV-RNA, and baseline CD4 count, odds of CD4 recovery \u3c 500 cells/mm3 were higher in those with baseline CD4/CD8 ratio \u3c 1 (odds ratio 3.2, p=0.01), on-ART CD4/CD8 ratio \u3c 1 (odds ratio 2.4, p=0.007), and on-ART CD8 count \u3c 500 cells/mm3 (odds ratio 3.1, p=0.0005). Results, Project 2: 204 participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. The participants were 98% male (199/204) with median age 26 years and baseline Fiebig stage 3 (96/204, 47%), CD4 count 386 cells/mm3, and plasma HIV RNA 5.87 log10 copies/mL. ART was started at a median of 19 days post estimated infection. At baseline, 126/165 participants (76%) had quantifiable CSF HIV RNA (median 3.13 log10 copies/mL). At week 24 (n=90), two participants (2%) had quantifiable CSF HIV RNA, with one case of CSF escape identified with plasma HIV RNA \u3c 50 copies/mL and CSF HIV RNA 2.50 log10 copies/mL. At week 96 (n=55), one participant (2%) had quantifiable CSF HIV RNA, which did not meet criteria for CSF escape. The two other cases of quantifiable CSF HIV RNA were due to plasma HIV RNA \u3e CSF HIV RNA. The participant with CSF escape was treated with efavirenz, tenofovir, and lamivudine and had a CD4 count of 840 cells/mm3 and CSF WBC and CSF protein of 4 cells/mm3 and 30 mg/dL. His MRI at week 24 showed a small nonspecific T2/FLAIR hyperintense focus in the right high frontal white matter. He did not have a lumbar puncture performed at baseline nor at subsequent visits. Conclusions: Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery is observed in rare individuals, associated with low pre-ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment. While levels of CSF HIV RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first two years of ART. The low rate of CSF escape may also be impacted by high levels of adherence to ART in this cohort or the short duration of ART. Longitudinal monitoring will be required to verify if CSF escape remains rare under long-term ART in early treated individuals

METODE ITERASI UNTUK PENGEMBANGAN GAME RPG STUDI KASUS GAME PANGERAN DIPONEGORO

RPG (Role Playing Game) adalah salah satu jenis aliran game dimana pemain mengontrol satu atau lebih karakter yang biasanya dirancang oleh pemain dan menggunakannya untuk menyelesaikan serangkaian misi. RPG mempunyai unsur-unsur cerita kompleks dan sifat unik yang dapat menarik perhatian pemainnya untuk memerankan seorang karakter dalam game tersebut. Hal ini membuat terciptanya sebuah ide untuk membangun game RPG dengan menerapkan metode iterasi dalam pengembangannya. Metode iterasi akan melalui 4 tahapan secara berurutan, yaitu tahapan desain, tahapan penerapan, tahapan pengujian, dan tahapan evaluasi. Game maker yang digunakan untuk membangun game ini adalah RPG Maker XP dengan bahasa pemrograman Ruby. Hasil akhir penelitian menunjukkan bahwa game Pangeran Diponegoro berjalan dengan baik tanpa ada kendala dan sudah layak untuk dimainkan oleh publik. Penggunaan metode iterasi dan RMXP sudah cukup efektif dan efisien dalam pengembangan game berjenis aliran RPG yang berbasis desktop. Selain dapat dijadikan sebagai media hiburan, game ini juga dapat dijadikan sebagai media pembelajaran dan sumber referensi untuk penelitian berikutnya. Kata kunci: Game, Iterasi, RPG, RPG Maker XP, Ruby

Performance of an Existing Reinforced Concrete Building Designed in Accordance to Older Indonesian Seismic Code : A Case Study for a Hotel in Kupang, Indonesia

The recent seismic code SNI 1726-2012 is significantly different compared to the older code SNI 1726-2002. The seismic hazard map was significantly changed and the level of maximum considered earthquake was significantly increased. Therefore, buildings designed according to outdated code may not resist the higher demand required by newer code. In this study, seismic performance of Hotel X in Kupang, Indonesia which was designed based on SNI-1726-2002 is investigated. The structure was analyzed using Nonlinear Time History Analysis. The seismic load used was a spectrum consistent ground acceleration generated from El-Centro 18 May 1940 North-South component in accordance to SNI 1726-2012. The results show that Hotel X can resist maximum considered earthquake required by SNI 1726-2012. The maximum drift ratio is 0.81% which is lower than the limit set by FEMA 356-2000 (2%). Plastic hinge damage level is also lower than the allowance in ACMC 2001

APLIKASI SISTEM PERINGATAN TABRAKAN PADA KAPAL BERBASIS DATA GPS MENGGUNAKAN LOGIKA FUZZY

Automatic Identification System (AIS)  is an important equipment in ship for giving ship’s information to other ships or harbour. Unfortunately, there is still no ship collision warning system included in AIS. Hence, an application of ship collision early warning system based on Global Positioning System (GPS) data is proposed in this paper. Here, the zero-order sugeno fuzzy logic is used to process the ships speed and position data. The output of this warning system are recommended ships speed and heading direction to prevent the ship collision based on IMO (International Maritime Organization) regulation. The object used is a ship prototype equiped with GPS. The testing is held in four position of the ship prototype againts static object. The positions are -45o, -25o, 25o dan 45o. The testing results yield 100% accuracy to the IMO regulation of the head on situations case

CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the {\beta}-globin locus

The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the 3-dimensional folding of a 1 Mbp region of human chromosome 11 containing the {\beta}-globin genes by integrating looping interactions of the insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a polymer model of chromatin. We find that CTCF-mediated cell type specific interactions in erythroid cells are organized to favor contacts known to occur in vivo between the {\beta}-globin locus control region (LCR) and genes. In these cells, the modeled {\beta}-globin domain folds into a globule with the LCR and the active globin genes on the periphery. By contrast, in non-erythroid cells, the globule is less compact with few but dominant CTCF interactions driving the genes away from the LCR. This leads to a decrease in contact frequencies that can exceed 1000-fold depending on the stiffness of the chromatin and the exact positioning of the genes. Our findings show that an ensemble of CTCF contacts functionally affects spatial distances between control elements and target genes contributing to chromosomal organization required for transcription.Comment: Full article, including Supp. Mat., is available at Nucleic Acids Research, doi: 10.1093/nar/gks53

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.This work was supported by the Australian National Health and Medical Research Council project grants [grant numbers 472640, 1024726 to W.G.T. and R.D.H]; and a project grant awarded to R.D.H, funded in Australia by the Captain Courageous Foundation (http://www.captaincourageousfoundation.com). R.D.H also holds an NHMRC senior research fellowship [grant number 1022402]

Diastolic dysfunction in pulmonary artery hypertension: Creatine kinase and the potential therapeutic benefit of beta‐blockers

Passive properties of the myocardium influence diastolic filling and cardiac output. In heart failure, changes in contributors to the passive properties of the ventricle, such as titin and collagen, and loss of the metabolic enzyme creatine kinase, increase resistance to filling resulting in diastolic dysfunction. Pulmonary artery hypertension (PAH) arises from interactions between the pulmonary vasculature and the right ventricle (RV) which ultimately leads to RV failure. Beta1‐adrenergic receptor blockers (BB) act on the myocardium and are beneficial in left heart failure but are not used in PAH. We investigated whether BB improved survival and RV function in a rat model of PAH. Rats were injected with monocrotaline (60 mg/kg) to induce PAH and RV failure, or saline as controls (CON). When PAH was established, rats were treated with metoprolol (10 mg/kg per day) (MCT+BB) or vehicle (sucrose) (MCT); CON were treated with vehicle. In vivo measurement of RV compliance using pressure–volume catheter, indicated diastolic dysfunction in the RV of MCT rats was improved with BB treatment. Expression of creatine kinase protein and mRNA was lower in MCT rats compared to CON, with a trend for reversion by BB treatment. Isolated CON RV myocytes had a positive contraction response to faster pacing, whereas it was negative in MCT. MCT+BB cells had an intermediate response, indicating improved ability to respond to increased demand. BB improved diastolic function, partially restored metabolic enzymes and augmented contractility in PAH. These data support the hypothesis that BB may be beneficial in PAH by supporting RV function

Tracking smell loss to identify healthcare workers with SARS-CoV-2 infection

Introduction Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. Methods and findings We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV- 2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01). Conclusions In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms

Functional annotation of human long noncoding RNAs via molecular phenotyping

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-todate lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.Peer reviewe

BLUE OCEAN STRATEGY FORMULATION IN HOTEL INDUSTRY: The Case of Grage Ramayana Hotel

This research intends to apply the blue ocean strategy in the context of hotel industry in Yogyakarta. Hotel industry currently experiences the intense competition, while competitors tend to face the competition by using the similar strategic profile (value curve) based on their star classification and pricing-policy. As the implication, the market segment is based on star classificatio