Portable Smart-Space Research Interface to Predetermine Environment Acoustics for Cochlear implant and Hearing aid users with CCi-MOBILE

Internet of issues (IoT) in healthcare, has effi-ciently accelerated medical monitoring and evaluation by the real-time evaluation of collected knowledge. Hence, to assist the hearing-impaired group with higher calibrations to their medical processors and listening to aids, a conveyable sensible house interface – AURIS has been developed by the Cochlear Implant Processing Lab (CILab) at UT-Dallas. The proposed Auris interface periodically samples the acoustic house, and by a be taught vs check part, builds a Gaussian combination mannequin for every particular environmental areas. An efficient connection is established by the Auris interface with the CRSS CCi-Mobile analysis platform by an android app to fantastic tune the con-figuration settings for cochlear implant (CI) or listening to aid (HA) users coming into the room/location.

Baseline goal evaluations have been carried out in various naturalistic areas utilizing 12 hours of audio knowledge. The efficiency metrics is decided by a verified wi-fi communication, alongside with estimated acoustic surroundings information and room classification at higher than 90% accuracy. Online analysis has develop into a important recruitment modality for understanding and lowering well being disparities amongst hidden populations most in danger for HIV an infection. There is a scarcity of consensus and pointers for the accountable conduct of on-line recruitment for HIV danger populations. Using semi-structured cellphone interviews, this examine drew on the experiences of principal investigators (PIs) engaged in on-line HIV analysis to illuminate scientific and moral advantages and challenges of social media recruitment. Using Thematic Analysis 5 main themes emerged: sampling benefits and disadvantages; challenges of knowledge integrity; management of privateness protections; researcher competence and duty; and sources.

The feasibility of recruiting and retaining males who’ve intercourse with males and transgender girls in a multinational potential HIV prevention analysis cohort examine in sub-Saharan Africa (HPTN 075)

Introduction: Men who’ve intercourse with males (MSM) and transgender girls (TGW) in sub-Saharan Africa (SSA) are profoundly affected by HIV with excessive HIV prevalence and incidence. This inhabitants additionally faces robust social stigma and authorized boundaries, doubtlessly impeding participation in analysis. To date, few multi-country longitudinal HIV analysis research with MSM/TGW have been performed in SSA. Primary goal of the HIV Prevention Trials Network (HPTN) 075 examine was to assess feasibility of recruiting and retaining a multinational potential cohort of MSM/TGW in SSA for HIV prevention analysis.

Methods: HPTN 075, performed from 2015 to 2017, was designed to enroll 400 MSM/TGW at 4 websites in SSA (100 per website: Kisumu, Kenya; Blantyre, Malawi; Cape Town, South Africa; and Soweto, South Africa). The variety of HIV-positive individuals was capped at 20 per website; HIV-positive individuals already in care had been excluded from participation. The one-year examine included 5 biobehavioural assessments. Community-based enter and danger mitigation protocols had been included in examine design and conduct.Results: Of 624 individuals screened, 401 had been enrolled. One in 5 contributors was categorized as transgender. Main causes for ineligibility included: (a) being HIV constructive after the cap was reached (29.6%); (b) not reporting anal intercourse with a person within the previous three months (20.6%); and (c) being HIV constructive and already in care (17.5%).

Five (1.2%) contributors died through the examine (unrelated to examine participation). 92.9% of the eligible contributors (368/396) accomplished the ultimate examine go to and 86.1% participated in all visits. The foremost, overlapping causes for early termination included being (a) unable to adhere to the go to schedule, predominantly due to relocation (46.4%), and (b) unable to contact the participant (32.1%). Participants reported robust motivation to take part and few participation boundaries. Four contributors reported social harms (lack of confidentiality and sexual harassment by examine workers) that had been efficiently addressed.

Conclusions: HPTN 075 efficiently enrolled a multinational pattern of MSM/TGW in SSA in a potential HIV prevention analysis examine with a excessive retention price and few documented social harms. This helps the feasibility of conducting large-scale analysis trials on this inhabitants to handle its pressing, unmet HIV prevention wants.

 Portable Smart-Space Research Interface to Predetermine Environment Acoustics for Cochlear implant and Hearing aid users with CCi-MOBILE
Portable Smart-Space Research Interface to Predetermine Environment Acoustics for Cochlear implant and Hearing aid users with CCi-MOBILE

A scoping overview of sexual transmission associated HIV analysis amongst key populations in Malaysia: Implications for interventions throughout the HIV care cascade

The Malaysian authorities has dedicated to ‘Fast Tracking the HIV Response’ to obtain UNAIDS 2030 targets to finish AIDS. The epidemic is concentrated amongst key populations and has shifted from individuals who inject medicine to HIV an infection by sexual transmission amongst males who’ve intercourse with males, intercourse staff and transgender folks. The goal of this scoping overview was to look at social and behavioural analysis printed since 2005 that may inform understanding of every stage of the 90:90:90 remedy cascade (as proposed by UNAIDS), together with HIV danger behaviours and testing practices that precede entry.

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We discovered a focus of research associated to predictors or correlates of HIV infections (principally amongst males who’ve intercourse with males) and a shortfall in literature pertaining to intercourse staff or transgender folks. While a number of research examined elements related with HIV testing, just one examined uptake of antiretroviral remedy and two explored problems with remedy adherence. No examine examined broader care and assist of individuals dwelling with HIV. To scale-up efficient programmes and apprise funding to obtain the formidable targets set-out within the Malaysian National HIV/AIDS Strategic Plan, a mix of complete strategic info and proof generated by major analysis is important.

Fertility Desire in HIV/AIDS Research During 1992-2019: A Systematic Text Mining of Global Literature

There has been a rise of fertility need amongst folks residing with HIV/AIDS (PLWH) due to the development of HIV therapy and prevention of mother-to-children transmission applications. However, the event of analysis specializing in this matter over the previous three a long time shouldn’t be effectively documented. We aimed to discover the development of world publications concerning fertility needs amongst PLWH and determine their contents by way of the pure language processing method. Dataset from 1992 to 2019 was downloaded utilizing the Web of Science Core Collection. Bibliometric indicators akin to change in whole publications, citations, and nations’ collaboration had been examined.

Main matters of chosen publications had been decided utilizing the latent Dirichlet allocation. There had been 303 articles revealed throughout the interval 1992-2019, with a speedy improve in the quantity of publications in the previous 5 years. Common themes included determinants of fertility need, HIV prevention for adolescents, and safer conception for {couples} affected with HIV. However, publications on HIV care and antenatal care for ladies with HIV had been nonetheless restricted. Findings prompt a name for the long run assist and collaborations for fertility intention, in addition to the promotion of HIV care and repair for adolescents and pregnant girls with HIV, particularly in nations with poor sources and a excessive burden of HIV/AIDS.

HIV and three dimensions of wiessdom: Association with cognitive perform and bodily and psychological well-being: For: Psychiatry Research

Wisdom is a novel human persona trait with cognitive, affective or compassionate, and reflective dimensions. We evaluated relationships of three particular dimensions of knowledge with cognitive perform and bodily and psychological well-being in folks with HIV (PWH) and HIV-negative (HIV-) members. Subjects included 138 adults (61 PWH, 77 HIV-) from the San Diego group. Validated measures had been used to evaluate knowledge and well-being. Cognitive perform was assessed by way of the Montreal Cognitive Assessment.

We performed multivariate linear regressions to guage the associations of knowledge dimensions with cognitive perform and bodily and psychological well-being. Compared to the HIV- group, PWH had decrease imply scores on cognitive perform, and bodily and psychological well-being, and cognitive and reflective dimensions of knowledge, however related scores on affective or compassionate knowledge. Among PWH, larger whole knowledge scores had been related to older age, decrease probability of substance dependence, higher psychological well-being, higher cognitive perform, larger resilience, social assist, and optimism scores, in addition to decrease ranges of perceived stress and nadir CD4 depend. Our findings of an affiliation of completely different dimensions of knowledge with bodily and/or psychological well-being in PWH would level to a chance that enhancing these dimensions of knowledge would possibly enhance well being outcomes in PWH.

 Fertility Desire in HIV/AIDS Research During 1992-2019: A Systematic Text Mining of Global Literature
Fertility Desire in HIV/AIDS Research During 1992-2019: A Systematic Text Mining of Global Literature

Formative analysis to tell the event of a peer-led HIV self-testing intervention to enhance HIV testing uptake and linkage to HIV care amongst adolescents, younger folks and grownup males in Kasensero fishing group, Rakai, Uganda: a qualitative examine

Background: Despite efforts to enhance HIV testing and linkage to HIV care amongst adolescents, younger folks and grownup males, uptake charges stay beneath world targets. We performed formative analysis to generate knowledge essential to tell the design of a peer-led HIV self-testing (HIVST) intervention supposed to enhance HIV testing uptake and linkage to HIV care in Kasensero fishing group in rural Uganda.

Methods: This qualitative examine was performed in three examine communities in Kasensero fishing group in Rakai district, Uganda, in May 2019. Six single-sex focus group discussions (FGDs) comprising 7-Eight members had been performed with adolescents and younger folks (15-24 years) and grownup males (25+ years). We collected knowledge on folks’s perceptions about peer-led HIVST; potential acceptability of a peer-led HIVST intervention and strategies on learn how to enhance linkage to HIV care after a optimistic HIVST outcome. Peer-led HIVST was outlined as an method the place educated lay folks distribute HIVST kits to different folks in the group. FGDs had been audio-recorded with permission from the members, transcribed verbatim and analysed manually following a thematic framework method.

Results: Forty-seven members (31 males and 16 girls) participated in the FGDs. Across communities and age-groups, most members talked about that peer-led HIVST can be usually acceptable to folks in the fishing group however folks will want assist in performing the check as a result of concern of performing the check wrongly or failing to deal with HIV-positive outcomes. Most members felt that peer-led HIVST would convey HIV testing companies nearer to the group “as a result of [the peer-leader] might be my fast neighbour”, making it simpler for folks to acquire the kits at any time of their comfort. To enhance linkage to HIV care, members felt that the use of peer-leaders to ship the preliminary ART dose to self-tested HIV-positive people can be extra preferable to the use of community-based ART teams or home-based ART initiation.

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Conclusion: Our examine exhibits that peer-led HIVST is doubtlessly acceptable in the fishing group. These findings counsel that this method can enhance uptake of HIV testing and linkage to HIV care companies amongst populations which are normally missed by way of standard HIV testing companies.

The HIV-1 Transgenic Rat: Relevance for HIV Noninfectious Comorbidity Research

HIV noninfectious comorbidities (NICMs) are a present healthcare problem. The state of affairs is additional sophisticated as there are only a few efficient fashions that can be utilized for NICM analysis. Previous analysis has supported using the HIV-1 transgenic rat (HIV-1TGR) as a mannequin for the examine of HIV/AIDS. However, further research are wanted to substantiate whether or not this mannequin has options that may help NICM analysis. An indication of the utility of the HIV-1TGR mannequin can be to indicate that the HIV-1TGR has mobile receptors capable of bind HIV proteins, as this may be related for the examine of cell-specific tissue pathology. In reality, an elevated frequency of HIV receptors on a particular cell sort could enhance tissue vulnerability since binding to HIV proteins would ultimately lead to cell dysfunction and demise. Evidence means that observations of selective mobile vulnerability on this mannequin are per some particular tissue vulnerabilities seen in NICMs. We recognized CXCR4-expressing cells within the mind, whereas particular markers for neuronal degeneration demonstrated that the identical neural varieties had been dying. We additionally affirm the presence of gp120 and Tat by immunocytochemistry within the spleen, as beforehand reported.

However, we noticed very uncommon constructive cells within the mind. This underscores the purpose that gp120, which has been reported as detected within the sera and CSF, is a possible supply to which these CXCR4-positive cells are uncovered. This various seems extra possible than the native manufacturing of gp120. Further research could point out some degree of native manufacturing, however that won’t remove the position of receptor-mediated pathology. The binding of gp120 to the CXCR4 receptor on neurons and different neural cell varieties within the HIV-1TGR can thus clarify the phenomena of selective cell demise. Selective mobile vulnerability could also be a contributing issue to the event of NICMs. Our knowledge point out that the HIV-1TGR could be an efficient mannequin for the research of HIV NICMs due to the distinction within the regional expression of CXCR4 in rat tissues, thus resulting in particular organ pathology. This additionally means that the mannequin can be utilized within the improvement of therapeutic choices.

Craniofacial morphology of HIV-infected adolescents present process extremely lively antiretroviral remedy (HAART): An authentic analysis

Objectives: To analyze the craniofacial morphology in youngster sufferers and adolescents by evaluating the skeletal cephalometric profile of the HIV contaminated sufferers on this age group and evaluating them with the HIV-negative controls.Materials and strategies: The current examine was a deliberate case-control examine which included 25 HIV-positive adolescent sufferers aged between 10 and 18 years (the examine group) who had been in contrast with 25 age- and sex-matched HIV-negative adolescent controls (the management group). All the sufferers had been HIV contaminated through a vertical transmission with constructive serology confirmed in two completely different assessments and had been stored on HAART since they had been born.

The diagnostic aids used for orthodontic documentation included facial images, digital orthopantomographs, lateral teleradiographs, and examine fashions.Results: With reference to the methodologies used for taking the cephalometric values, all of the strategies used had been in sturdy settlement with one another for nearly all of the variables studied and had excessive intra-class correlation coefficient values besides Co-A, SN.ANSPNS, and SNB which, too, had a very good settlement of 60%. Nevertheless, the settlement was constructive for these variables, too, for the reason that P values obtained had been discovered to be statistically important (P < 0.05).

Conclusion: Most of the measurements within the HIV-infected adolescents had been discovered to be just like those obtained for the HIV-negative controls, though, the examine outcomes highlighted the importance of additional research to be carried out on this regard, particularly, the longitudinal examine designs whereby the mentioned variables could be studied on a follow-up foundation in longitudinal research to have an thought of the precise adjustments noticed and their sample within the included teams.

The HIV-1 Transgenic Rat: Relevance for HIV Noninfectious Comorbidity Research
The HIV-1 Transgenic Rat: Relevance for HIV Noninfectious Comorbidity Research

Potential of Augmented Reality Platforms to Improve Individual Hearing Aids and to Support More Ecologically Valid Research

An augmented actuality (AR) platform combines a number of applied sciences in a system that may render particular person “digital objects” that may be manipulated for a given function. In the audio area, these could, for instance, be generated by speaker separation, noise suppression, and sign enhancement. Access to the “digital objects” might be used to reinforce auditory objects that the person needs to listen to higher. Such AR platforms at the side of conventional listening to aids could contribute to closing the hole for folks with listening to loss by multimodal sensor integration, leveraging intensive present synthetic intelligence analysis, and machine-learning frameworks.

This might take the type of an attention-driven sign enhancement and noise suppression platform, along with context consciousness, which might enhance the interpersonal communication expertise in advanced real-life conditions. In that sense, an AR platform might function a frontend to present and future listening to options. The AR machine would improve the indicators to be attended, however the listening to amplification would nonetheless be dealt with by listening to aids. In this text, recommendations are made about why AR platforms could provide perfect affordances to compensate for listening to loss, and the way research-focused AR platforms might assist towards higher understanding of the position of listening to in on a regular basis life.HIV-1 an infection poses a serious menace to the general public well being worldwide.

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The antiretroviral brokers which are presently used to deal with HIV-1 an infection goal viral reverse transcriptase, integrase and protease, or block the fusion of viral envelop and cell membrane. Studies have proven that the HIV-1 encoded protein Nef performs an essential position within the pathogenesis of viral an infection. Nef ensures environment friendly counterattack towards host immune responses in addition to long-term evasion of immune surveillance. In addition, Nef, expressing at a excessive degree early within the viral life cycle, is required for sustaining a excessive viral load within the persistent an infection in vivo and for full pathologic potential. Therefore, Nef could also be a wonderful goal to deal with HIV-1 an infection.

Factors associated with attitudes towards HIV cure research among transgender women and travestis: a cross-sectional survey in São Paulo, Brazil

Objective: Characterising the perceptions of teams most affected by HIV is prime in establishing pointers for biomedical development. Although Brazil has efficiently fought HIV/AIDS by a number of measures, transgender women nonetheless have a chance of HIV an infection 55 instances increased than the overall inhabitants. This research aimed to higher perceive the notion and consciousness of HIV cure research among the trans-identifying inhabitants in São Paulo, Brazil, and to find out components that inspire or discourage participation in HIV cure research.Setting: This cross-sectional research analysed information collected from a questionnaire administered to 118 transgender women and travestis at 5 websites throughout the metropolis of São Paulo. It makes use of quantitative methodology to explain the views of transgender and travesti folks in relation to HIV cure research and the context in which such views are produced.

Results: Of 118 members, most members (73%) had some data of HIV cure research and had been most keen to take part in on-line surveys (52%), interviews (52%), focus teams (52%) and research involving blood attracts (57%). Those with a increased training or employment standing had been extra more likely to agree that somebody had been cured of HIV, folks residing with HIV are discriminated in opposition to, and extra details about HIV cure research is required earlier than the group embraces it. Only 55% of members fully trusted their doctor. The largest motivational components included gaining further data about HIV an infection (77%) and the potential for a longer, more healthy life for all (73%).

Conclusions: As a main evaluation of HIV cure attitudes among the transgender and travesti inhabitants in addition to the social context in which they’re shaped, this research identifies alternatives to strengthen the dialogue and develop extra academic collaborations between scientific investigators, group educators and the trans-identifying inhabitants to make sure that HIV cure research is inclusive of various views. mplementation of efficient behavioral research methods among HIV at-risk and contaminated AYA is vital to ending the HIV epidemic and necessitates profitable recruitment methods. A complete search was executed throughout 4 digital databases. Of the 1697 recognized research, seven met inclusion standards with six of those seven directed to HIV prevention. Most research used on-line recruitment as a part of a hybrid technique, and mixed field-based/in-person and on-line strategies. Recruitment methods and outcomes, assets and compensation, procedures for consent, and timelines different among all seven research. Our outcomes spotlight the necessity for growth of recruitment fashions in alignment with behavioral methods aimed to deal with and forestall HIV among US AYA.

Factors associated with attitudes towards HIV cure research among transgender women and travestis: a cross-sectional survey in São Paulo, Brazil
Factors associated with attitudes towards HIV cure research among transgender women and travestis: a cross-sectional survey in São Paulo, Brazil

Web-Based Data Collection for Older Adults Living With HIV in a Clinical Research Setting: Pilot Observational Study

Background: Longitudinal follow-up of older individuals residing with HIV is important for the ascertainment of aging-related scientific and behavioral outcomes, and self-administered questionnaires are crucial for gathering behavioral data in research involving individuals residing with HIV. Web-based self-reported information assortment outcomes in increased information high quality than paper-and-pencil questionnaires in a wide selection of populations. The possibility of distant web-based surveys may additionally improve retention in long-term research research. However, the acceptability and feasibility of web-based information assortment in scientific research involving older individuals residing with HIV have by no means been studied.

Objective: This research goals to evaluate the acceptability and feasibility of a web-based survey to gather data on sexual, substance use, and bodily exercise behaviors; examine the information high quality of the web-based survey with that of a paper-and-pencil questionnaire; and summarize web-based survey metrics.

Methods: This pilot research came about throughout the AIDS Clinical Trials Group A5322 research, a longitudinal cohort of males and women residing with HIV (aged ≥40 years), adopted at 32 scientific websites in the United States and Puerto Rico. A complete of four websites participated in this research. An internet-based survey was created utilizing self-administered questionnaires sometimes accomplished in A5322 through paper and pencil. Pilot research members accomplished these questionnaires through web-based survey at one research go to in lieu of paper-and-pencil administration. Two questions had been added to evaluate feasibility, outlined as members’ notion of the convenience of web-based survey completion (very arduous, arduous, straightforward, very straightforward), and their most well-liked format (pc or pill, paper and pencil, no choice) for finishing the questions in the longer term (acceptability). Feasibility and acceptability had been summarized total and by demographic and scientific traits; the proportion of evaluable information by web-based survey versus beforehand administered paper-and-pencil questionnaires (information high quality) was in contrast for every query.

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Results: Acceptability and feasibility had been excessive total: 50.0% (79/158) most well-liked pc or pill, 38.0% (60/158) reported no choice, and 12.0% (19/158) most well-liked paper and pencil; 93.0% (147/158) reported survey completion straightforward or very straightforward. Older age was associated with decrease odds of preferring pc or pill to paper and pencil (odds ratio per 1-year improve in age: 0.91, 95% CI 0.85-0.98). Individuals who discovered the survey arduous or very arduous had a decrease median neurocognitive take a look at rating than those that discovered it straightforward or very straightforward. Data high quality with web-based survey administration was much like or increased than that with paper-and-pencil administration for many questions.Conclusions: Web-based survey administration was acceptable and possible in this cohort of older adults residing with HIV, and information high quality was excessive. Web-based surveys will be a great tool for legitimate information assortment and can probably enhance retention in long-term follow-up research.

COVID-19 antibody development fueled by HIV-1 broadly neutralizing antibody research

Purpose of assessment: The coronavirus illness 2019 (COVID-19) pandemic has caught the world unprepared, with no prevention or remedy methods in place. In addition to the efforts to develop an efficient vaccine, various approaches are important to manage this pandemic, which can almost definitely require a number of available options. Among them, monoclonal anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been remoted by a number of laboratories in document time facilitated by strategies that had been first pioneered for HIV-1 antibody discovery. Here, we summarize how classes discovered from anti-HIV-1 antibody discovery have offered elementary information for the speedy development of anti-SARS-CoV-2 antibodies.

Recent findings: Research laboratories that efficiently recognized potent broadly neutralizing antibodies towards HIV-1 have harnessed their antibody discovery strategies to isolate novel potent anti-SARS-CoV-2 antibodies, which have efficacy in animal fashions. These antibodies symbolize promising medical candidates for remedy or prevention of COVID-19.Summary: Passive switch of antibodies is a promising method when the elicitation of protecting immune responses is troublesome, as within the case of HIV-1 an infection. Antibodies can even play a major function in post-exposure prophylaxis, in high-risk populations that will not mount sturdy immune responses after vaccination, and in remedy. We present a assessment of the latest approaches used for anti-SARS-CoV-2 antibody discovery and upcoming challenges within the discipline.

“[It] is now my duty to satisfy that want:” Clinical and speedy post-mortem employees members’ experiences and perceptions of HIV reservoir research on the finish of life

Introduction: Little is understood in regards to the results of HIV reservoir research on the finish of life on employees members concerned. Staff members’ perceptions and experiences had been assessed associated to their involvement within the Last Gift, a speedy post-mortem examine on the University of California San Diego enrolling individuals dwelling with HIV who’re terminally sick and have a want to contribute to HIV cure-related research.Methods: Two focus group discussions consisting of medical (n = 7) and speedy research post-mortem (n = 8) employees members had been carried out to grasp the views of employees members and the influence the Last Gift speedy post-mortem examine had on them. The complete pattern consisted of 66.7% females and 33.3% males and was ethnically numerous (66.7% Caucasian, 6.7% African American, 20.0% Asian descent, 6.7% Hispanic descent and American Indian) with a variety of expertise within the HIV discipline from 1 12 months to 30 years.

Results: Qualitative focus group information revealed 5 main themes underlying examine employees members’ multilayered psychological and sensible involvement: 1) constructive perceptions of the Last Gift examine, with sub-themes together with Last Gift examine members’ altruism, achievement, and management on the finish of life, 2) perceptions of employees members’ shut involvement within the Last Gift examine, with sub-themes associated to employees members’ cognitive processing, self-actualization and achievement, stress administration and resilience, coping mechanisms, and gratitude towards Last Gift members and towards the examine itself, 3) issues for profitable and sustainable examine implementation, akin to moral consciousness and sustained neighborhood and affected person engagement, 4) collaborative studying and organizational processes and the worth of interdependence between employees members, and 5) issues for potential examine scale-up at different medical research websites.Discussion: Understanding employees members’ nuanced emotional and procedural experiences is essential to the Last Gift examine’s sustainability and can inform comparable remedy research research carried out with individuals dwelling with HIV on the finish of life. The examine’s potential reproducibility will depend on a sturdy research infrastructure with established, interdependent medical and speedy post-mortem groups, steady neighborhood engagement, and an moral and well-informed engagement course of with individuals dwelling with HIV.

COVID-19 antibody development fueled by HIV-1 broadly neutralizing antibody research
COVID-19 antibody development fueled by HIV-1 broadly neutralizing antibody research

Adaptation of the AID system for stem cell and transgenic mouse research

The auxin-inducible degron (AID) system is changing into a broadly used technique for speedy and reversible degradation of goal proteins. This system has been efficiently used to review gene and protein features in eukaryotic cells and customary mannequin organisms, akin to nematode and fruit fly. To date, functions of the AID system in mammalian stem cell research are restricted. Furthermore, customary mouse fashions harboring the AID system haven’t been established. Here we’ve explored the utility of the H11 safe-harbor locus for integration of the TIR1 transgene, a vital part of auxin-based protein degradation system. We have proven that the H11 locus can assist constitutive and conditional TIR1 expression in mouse and human embryonic stem cells, in addition to in mice.

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We reveal that the AID system will be efficiently employed for speedy degradation of steady proteins in embryonic stem cells, which is essential for investigation of protein features in shortly altering environments, akin to stem cell proliferation and differentiation. As embryonic stem cells possess limitless proliferative capability, differentiation potential, and might mimic organ development, we consider that these research instruments will probably be an relevant useful resource to a broad scientific viewers.

Axela Inc. DNA Research

April 2010
Axela Inc. announces bilateral agreement with diagnostic provider Salomao and Zoppi and Cria Opportunities Inc.

Axela Inc, the Toronto-based producer of multiplex biomarker tools for proteins, DNA and RNA in research and diagnostics, Salomao and Zoppi (S&Z), one of the largest diagnostics providers in Sao Paulo Brazil, and innovations management firm Cria Opportunities Inc (CRIA), have signed a memorandum of understanding to commercialize Axela’s technology in Brazil and South America.

June 2009

Xceed Meets HTX/CIHR Grant Milestone: Decreasing Sample-Prep Time From Days to Less Than Eight Hours
Xceed Molecular announced that it has met the goals of a $127,000 HTX/CIHR grant, reducing sample-preparation time from 2.5 days to less than eight hours.

October 2008

James L. Wittliff, Ph.D., FACB, to Present “Predicting Breast Cancer Outcome with Gene Expression Signatures on the Ziplex® System at the Association for Molecular Pathology Conference, October 30
Xceed Molecular announced that renowned breast cancer researcher and Xceed collaborator, Dr. James L. Wittliff, a professor in the Department of Biochemistry and Molecular Biology at the University of Louisville, will be a featured speaker at the Association for Molecular Pathology (AMP) Annual Meeting.

September 2008

Mt. Sinai Services Toronto Becomes An Xceed Authorized Gene-Expression Service Provider Using Ziplex® System
Xceed Molecular announced that the Mt. Sinai Services unit of the Mt. Sinai Hospital in Toronto, Canada, has become an authorized provider of gene-expression services using Xceed’s
Ziplex System.

Queen’s University Chooses Xceed’s Ziplex® System for Translational Research
Xceed Molecular announced that Queen’s University in Kingston, Ontario, Canada, is the latest high-profile institution to implement Xceed’s Ziplex System as a critical tool to advance its translational research.

August 2008

Xceed Ziplex® System for Automated Gene-Expression Analysis Wins 2008 R&D; 100 Award
Xceed Molecular announced that R&D; Magazine has selected the company’s Ziplex System as a recipient of the magazine’s prestigious R&D; 100 Award.

July 2008

Xceed Molecular to Launch New Inflammation Xpress Chip™ for the Ziplex® Automated Gene-Expression Analysis System at Clinical Lab Expo 2008, Booth 2155
Xceed Molecular will launch its new Inflammation Xpress Chip, a pre-configured array for use with the company’s Ziplex automated gene-expression analysis system, at the 2008 AACC/ASCLS Clinical Lab Expo (booth 2155).

June 2008

Xceed Molecular Licenses Signature from Moffitt Cancer Center and Adds Moffitt to Strategic Collaborator Program
Xceed Molecular announced that the Mt. Sinai Services unit of the Mt. Sinai Hospital in Toronto, Canada, has become an authorized provider of gene-expression services using Xceed’s
Ziplex System.

Xceed Molecular Grants Gen-Probe License to Xceed’s Flow-Thru Chip® Technology for Multiplex Molecular Diagnostics
Xceed Molecular has granted Gen-Probe Incorporated (Nasdaq: GPRO) and its affiliates a non-exclusive license to use Xceed’s novel Flow-Thru Chip technology.

May 2008

Xceed Molecular Features Ziplex® Automated Gene-Expression System at the Biomarker World Congress, Booth 16
Xceed’s Dr. David Englert and Dr. Zhe Zhang of Children’s Hospital of Philadelphia will present data at a luncheon workshop on Wednesday, May 21st

April 2008

Xceed Molecular Signs University of Florida to Strategic Collaborator Program; Focus on Developing New Molecular Test to Diagnose Early-Stage Bladder Cancer
Xceed Molecular announced that the University of Florida has joined Xceed’s Strategic Collaborator program. Xceed will work with primary researchers, Charles Joel Rosser, MD (Department of Urology) and Steve Goodison, MD (Department of Surgery), to perform initial verification and validation of an expression signature that has shown promise as a way to differentiate bladder cancer from other conditions using voided urine samples.

November 2007

Xceed Molecular Launches Strategic Collaborator Program; Signs Center for Molecular Medicine as its Inaugural Partner
Xceed Molecular announced that the company has launched its Strategic Collaborator program and signed its first member, the Center for Molecular Medicine (CMM), of Grand Rapids, Michigan. Specific terms were not disclosed.

Xceed Molecular Launches Ziplex® Automated Gene-Expression System at the Association for Molecular Pathology, Booth 84/85
Xceed Molecular announced that the company will launch its Ziplex Automated Gene Expression System for research use only at the Association for Molecular Pathology (AMP) Annual Meeting and Exhibit, which opens today at the Hyatt Regency Century Plaza Hotel in Los Angeles.

October 2007

Xceed Molecular Names Fran Tuttle to its Board of Trustees
Xceed Molecular Corporation announced today that Fran Tuttle has been appointed to Xceed’s board of directors.

Xceed Molecular to Debut RUO Ziplex Array
One year after rechristening itself Xceed Molecular to emphasize its orientation towards the clinical diagnostics market, the company formerly known as Metrigenix is preparing to launch a low-throughput and relatively affordable microarray platform called Ziplex next month.

February 2007

Xceed Molecular names David Deems President, and Michael L. Cohen, Chairman of the Board.
Xceed Molecular announced today that David Deems has been appointed company president with full executive responsibility for strategic, commercial, and operational development,
effective immediately.

October 2006

MetriGenix Changes Name to Xceed Molecular, Focuses on Translating Novel Biomarker-based Tests from Research into Routine Clinical Use
MetriGenix Corp. announced today that it has changed its name to Xceed Molecular.

December 2005

Appointment of Susan Bromley
Susan Bromley Named Vice President Diagnostic Product Development of MetriGenix, Inc.

June 2005

MetriGenix Completes Acquisition of GeneXP Biosciences
MetriGenix, Inc. announced that it has completed the acquisition of Woburn, Massachusetts-based GeneXP Biosciences, Inc.

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Introduction to multiplex immunohistochemistry

For the development of new immunotherapies, it is essential to research the tumor microenvironment. Immunohistochemistry is a versatile technique for studying the expression, distribution and activation of proteins in situ. For the detection of antigens, specific antibodies are used on thin cross-sections made of shock-frozen or formaldehyde-fixed, paraffin-embedded tissue. The visualization of the antigen is made possible by enzymatic reactions which lead to the precipitation of dye at the site of the antibody-antigen binding, or by fluorescent reporters. Fluorescent reporters can either be conjugated directly to the primary antibody (direct immunofluorescence) or to a secondary antibody that recognizes the species-specific primary antibody (indirect immunofluorescence). The last variant is the more frequently used method, since it still delivers signals with very small amounts of antigen.

In the past, this technique was used individually for each immune marker. Recently, molecular histopathology has evolved from single marker immunohistochemistry to multiplex marker detection. Multiplex immunohistochemistry, also called multiple immunolabeling or multiplex immunostaining, can maximize the amount of data obtained from a single sample. This is particularly important in cases where the amount of sample is limited, such as a tumor biopsy. In contrast to next generation sequencing or mass spectrometry, the spatial arrangement of proteins as well as protein interactions and co-localization can be examined in multiplex immunohistochemistry.

Chromogenic detection is in principle compatible with multiplex immunohistochemistry, but indirect labeling techniques with tyramide-based fluorescence have several advantages. The signal is amplified by the deposition of fluorophore-conjugated tyramide at the antigen binding site. Tyramid Signal Amplification (TSA) enables the detection of very rare targets in a sample and improves the fluorescence signal. It is also important that TSA also allows the use of unlabeled primary antibodies with the flexibility to use multiple antibodies from the same species.

Another not insignificant advantage of tyramide-based fluorescence detection is the resistance of the tyramide-antigen binding, which takes place through the covalent binding of tyrosine residues on or near the antigen. This resistance allows the removal of antibodies using heat, while maintaining the fluorescent signal of the antigen. With this method, different antibodies from the same host species can be used in succession without the otherwise expected cross-reactions. If additional, non-overlapping excitation and emission wavelengths are selected, it is easy to visualize different target proteins at the same time. Multispectral recordings allow the graphic isolation of fluorophores with partially overlapping spectra and the reduction of tissue autofluorescence.

The latest advances in multiplex immunohistochemistry and multispectral imaging enable the precise and simultaneous analysis of multiple tissue markers. For example, the analysis of proliferation and autophagy markers in the intestinal tissue can help with an accurate assessment of the epithelium turnover. In clinical application, the elucidation of the tumor microenvironment and the selection of targeted therapies can be improved by localizing and examining immuncheckpoint proteins. The applications of multiplex immunohistochemistry are versatile and include clinical, translational and basic research.

Detection of human CD3 (turquoise), CD8 (green), CD68 (orange), CK (red), Ki67 (yellow) and PD-L1 (white) in FFPE HNSCC with IHC-IF. Rabbit anti-CD3e recombinant monoclonal [BL-298-5D12], rabbit anti-CD8a recombinant monoclonal [BLR044F], mouse anti-CD68 monoclonal [KP-1], mouse anti-cytokeratin monoclonal [AE1 / AE3], rabbit anti-Ki67 monoclonal [BLR021E] and rabbit anti-PD-L1 recombinant monoclonal [BLR020E]. Secondary antibodies: HRP-conjugated goat anti-rabbit IgG and HRP-conjugated goat anti-mouse IgG. Substrate: Opal ™ 480, 520, 570, 620, 690 and 780. Counterstain: DAPI (blue).

Detection of human CD3 (yellow), CD8 (red), and CD20 (green) in FFPE tonsil by IHC-IF.

Detection of human CD3 (yellow), CD8 (red), and CD20 (green) in FFPE Mundel tissue with IHC-IF. Rabbit anti-CD3e recombinant monoclonal [BL-298-5D12], rabbit anti-CD8a recombinant monoclonal [BLR044F], mouse anti-CD20 monoclonal [L26]. Secondary antibodies: HRP-conjugated goat antirabbit IgG and HRP-conjugated goat anti-mouse IgG. Substrate: Opal ™ 520, 620, and 690. Counterstain: DAPI (blue).

Detection of human CD3 (yellow), CD20 (green), and CD68 (red) in FFPE lung carcinoma by IHC-IF.

Detection of human CD3 (yellow), CD20 (green), and CD68 (red) in FFPE lung cancer tissue with IHC-IF. Rabbit anti-CD3e recombinant monoclonal [BL-298-5D12], mouse anti-CD20 monoclonal [L26], and mouse anti-CD68 monoclonal [KP-1]. Secondary antibodies: HRP-conjugated goat antirabbit IgG and HRP-conjugated goat anti-mouse IgG. Substrate: Opal ™ 520, 620, and 690. Counterstain: DAPI (blue).

Required reagents
Component product
PathPlex ™ antibody panels
PathPlex ™ Panel 1 (CD3E, CD8 alpha, PD-L1)
PathPlex ™ Panel 2 (CD3E, CD8 alpha, CD20)
PathPlex ™ Panel 3 (CD3E, CD68, CD20)
PathPlex ™ Panel 4 (CD3E, Cytokeratin, CD8 alpha, CD68, PD-L1, FOXP3)
PathPlex ™ Panel 5 (CD3E, Cytokeratin, CD8 alpha, CD68, Ki-67, PD-L1)
PathPlex ™ Panel 6 (CD3E, Granzyme B, CD8 alpha, cytokeratin, Ki-67, SOX10)
PathPlex ™ Panel 7 (CD8 alpha, cytokeratin, CD45RO, CD4, FOXP3)
PathPlex ™ Panel 8 (CD3E, Cytokeratin, CD8 alpha, CD4, LAG3, FOXP3)
HRP-conjugated secondary antibodies (depending on primary antibodies)
Anti-Mouse IgG-heavy and light chain, HRP conjugated
Anti-Rabbit IgG-heavy and light highly cross-adsorbed, HRP conjugated
Opal dyes
Opal Polaris 480 (Akoya Biosciences)
 Opal 520 (Akoya Biosciences)
 Opal 540 (Akoya Biosciences)
 Opal 570 (Akoya Biosciences)
 Opal 620 (Akoya Biosciences)
 Opal 650 (Akoya Biosciences)
 Opal 690 (Akoya Biosciences)
 Opal Polaris 780 (Akoya Biosciences)
1x Plus Amplification Diluent
FP1498 (Akoya Biosciences)
DAPI
DAPI. dihydrochloride (AdipoGen Life Sciences)

Advantages of fluorescence multiplex immunohistochemistry using TSA
Fluorescence multiplex immunohistochemistry (mIHC) with tyramide signal amplification (TSA) has several advantages over one-color or traditional mIHC. The advantages below show what makes the mIHC with TSA a powerful technology for the visualization of several interesting target structures:

Visualization of multiple target structures within a single tissue section
This is crucial for experiments where the amount of sample is limited, e.g. for tumor biopsies or other clinical samples. mIHC enables the acquisition of the maximum amount of data from a single sample.

Investigation of the spatial arrangement of the target structures
The visualization of multiple targets within a single tissue section enables the spatial arrangement of the structures to be examined. This leads to a better understanding of protein interaction or co-localization within the conserved tissue architecture. This type of investigation is not possible with other techniques such as polymerase chain reaction, mass spectrometry or next-generation sequencing.

Further dynamic and linear measuring ranges
Compared to chromogenic detection, fluorophore detection offers a wider dynamic and linear measurement range, making it easier to visualize both high and low frequency targets on the same slide. The use of TSA also enables the signal amplification of targets with low frequency by amplifying the antigen-associated fluorescence signal.

Simplified panel design
The permanent existence of the covalent tyramide-tyrosine bond facilitates the heat-mediated removal of primary / secondary antibody pairs without interrupting the fluorescence signal. This means that any primary antibody validated for IHC, regardless of the host species, can be used for any target structure, as long as a specific secondary antibody is used.

Use of DAPI as counterstaining
Counterstaining the DNA with DAPI is preferable to hematoxylin because hematoxylin can be masked by other targets during chromogenic staining.

Spectral segregation
Spectral segregation ensures that the signals of each individual target structure can be distinguished from those of the other target structures. It also enables the subtraction of the signal caused by the autofluorescence of the tissue.

Rationalized quantification
The objective determination of the expression level of several targets can be standardized through the use of a suitable imaging platform and software. Since the tissue architecture is retained in the mIHC, the visualization of tissue reference points can also contribute to precise quantification.

Taken together, these features of fluorescent mIHC with TSA represent a robust approach to tissue analysis. Such analysis enables a variety of applications, such as the characterization of molecular signaling pathways, protein-protein interactions, the elucidation of the complex microenvironment of the tumor or the development of individually tailored therapeutic interventions.

Changes to Recommended Western Blotting Protocols

Cell Signaling Technology (CST) antibodies are validated utilizing our really useful western blotting protocol, developed and optimized by CST scientists. All knowledge proven on product webpages and datasheets was generated utilizing these protocols. We strongly suggest following our protocols to obtain optimum outcomes with all of our antibodies. Below are just a few examples of the results minor adjustments to the usual protocol could have in your outcomes.

Lysate Preparation

Sonication versus no sonication
Phospho-Histone H3 (Ser10) Antibody #9701

CKR/PAEC cell extracts

Primary Antibody Dilution Buffer

Milk versus BSA
Phospho-Akt (Ser473) Antibody #9271

C2C12 cells + insulin

Primary Antibody Incubation

Overnight at 4°C versus 2 hours at room temperature

Phospho-Akt (Ser473) Antibody #9271

HeLa cell extracts

PKCδ Antibody #2058

HeLa cell extracts

Phospho-GSK-3β (Ser9) Antibody #9336

HeLa cell extracts

Wash and Dilution Buffer

TBS-T versus PBS-T

Phospho-c-Jun (Ser63) II Antibody #9261
c-Jun (60A8) Rabbit mAb #9165
Ribosomal Protein S3 Antibody #2579
Calnexin (C5C9) Rabbit mAb #2679
Phospho-4E-BP1 (Thr37/46) (236B4) Rabbit mAb #2855

TBS-T (as really useful in CST protocol)
PBS-T (altered protocol)

Transfer and Antibody Incubations

Cell Signaling Technology recommends moist switch (as really useful by producer) adopted by one hour blocking and in a single day main antibody incubation at 4˚C.

iBlot® is a dry blotting system that completes switch in 7 minutes. SNAPi.d.™ is a vacuum operated incubation system, which reduces antibody incubation instances to lower than 30 minutes.

Phospho-p38 MAPK (Thr180/Tyr182) (3D7) Rabbit mAb #9215

Wet switch CST
 really useful incubations
iBlot® (fast transfer-Invitrogen) SNAPi.d.™ (fast incubations-Millipore) * decided optimum antibody focus for SNAPi.d.™

iBlot® is a trademark of Invitrogen Corporation.
SNAPi.d.™ is a trademark of Millipore Corporation.

Antiviral Articles

Process Chemistry in Antiviral Research.

Journal: Topics in current chemistry (Cham)Juli/19/2017
This article reviews antiviral therapies that have been approved for human use during the last decade, with a focus on the process chemistry that enabled access to these important drugs. In particular, process chemistry highlights from the practical syntheses of the HCV drugs sofosbuvir (Gilead), grazoprevir (Merck), and elbasvir (Merck), the HIV therapy darunavir (Tibotec) and the influenza treatment peramivir (BioCryst) are presented.
Yong-Li Zhong; Nobuyoshi Yasuda; Hongming Li; Mark McLaughlin; David Tschaen

Prevalence of etravirine (ETR)-RAMs at NNRTI failure and predictors of resistance to ETR in a large Italian resistance database (ARCA).

Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious DiseasesJuli/13/2014
The prevalence of drug resistance associated with the failure of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and the predictors of resistance to Etravirine (ETR) were assessed in 2854 subjects: 39 < 18 (paediatric) and 2815 ≥ 18 (adult) years old. These subjects failed to respond to their current NNRTI treatment, were three-class experienced and had been exposed to NNRTI for ≥3 months. A total of 1827 adult (64.9%) and 32 paediatric subjects (82.1%) harboured the virus with at least one ETR mutation. V179I, Y181C and G190A were the most frequent mutations in both groups. A significantly increased risk of ETR resistance with all three algorithms (Monogram (MGR) >3, Tibotec (TBT) >2 and enhanced MGR (ENH) ≥4) emerged in the paediatric population. Multivariate analysis revealed an increased risk of developing TBT >2 for NNRTI exposure, ENH ≥4 for NNRTI and EFV exposure in paediatric subjects; NVP exposure and higher (≥3.5 log10) HIV-RNA values for all three algorithms in adult subjects, whereas CD4 ≥ 200/μL appeared to be protective. The risk of being ETR resistant was more than doubled for paediatric vs. adult subjects, probably due to a more extensive use of NNRTI and an incomplete virological control.
S Rusconi; F Adorni; B Bruzzone; A Di Biagio; G Meini; A Callegaro+10 authors


Similar predictions of etravirine sensitivity regardless of genotypic testing method used: comparison of available scoring systems.

Journal: Antiviral therapyJuni/9/2013
BACKGROUND
The aims of this study were to compare various genotypic scoring systems commonly used to predict virological outcome to etravirine, and examine their concordance with etravirine phenotypic susceptibility.
METHODS
Six etravirine genotypic scoring systems were assessed: Tibotec 2010 (based on 20 mutations; TBT 20), Monogram, Stanford HIVdb, ANRS, Rega (based on 37, 30, 27 and 49 mutations, respectively) and virco(®)TYPE HIV-1 (predicted fold change based on genotype). Samples from treatment-experienced patients who participated in the DUET trials and with both genotypic and phenotypic data (n=403) were assessed using each scoring system. Results were retrospectively correlated with virological response in DUET. κ coefficients were calculated to estimate the degree of correlation between the different scoring systems.
RESULTS
Correlation between the five scoring systems and the TBT 20 system was approximately 90%. Virological response by etravirine susceptibility was comparable regardless of which scoring system was utilized, with 70-74% of DUET patients determined as susceptible to etravirine by the different scoring systems achieving plasma viral load <50 HIV-1 RNA copies/ml. In samples classed as phenotypically susceptible to etravirine (fold change in 50% effective concentration ≤3), correlations with genotypic score were consistently high across scoring systems (≥70%).
CONCLUSIONS
In general, the etravirine genotypic scoring systems produced similar results, and genotype-phenotype concordance was high. As such, phenotypic interpretations, and in their absence all genotypic scoring systems investigated, may be used to reliably predict the activity of etravirine.
Johan Vingerhoets; Steven Nijs; Lotke Tambuyzer; Annemie Hoogstoel; David Anderson; Gaston Picchio

TMC435 for the treatment of chronic hepatitis C.

Journal: Expert opinion on investigational drugsNovember/19/2012
BACKGROUND
Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV).
METHODS
TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 – 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date.
CONCLUSIONS
TMC435 is a ‘second-wave’ protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.
Sudeep Tanwar; Paul M Trembling; Geoffrey M Dusheiko


Short communication prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States.

Journal: AIDS research and human retrovirusesFebruar/22/2012
Abstract The prevalence of susceptibility to etravirine was investigated among clinical samples submitted for routine clinical testing in the United States using two separate weighted genotypic scoring systems. The presence of etravirine mutations and susceptibility to etravirine by phenotype of clinical samples from HIV-1-infected patients, submitted to Monogram Biosciences for routine resistance testing between June 2008 and June 2009, were analyzed. Susceptibility by genotype was determined using the Monogram and Tibotec etravirine-weighted genotypic scoring systems, with scores of ≤3 and ≤2, respectively, indicating full susceptibility. Susceptibility by phenotype was determined using the PhenoSense HIV assay, with lower and higher clinical cut-offs of 2.9 and 10, respectively. The frequency of individual etravirine mutations and the impact of the K103N mutation on susceptibility to etravirine by genotype were also determined. Among the 5482 samples with ≥1 defined nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations associated with resistance, 67% were classed as susceptible to etravirine by genotype by both scoring systems. Susceptibility to etravirine by phenotype was higher (76%). The proportion of first-generation NNRTI-resistant samples with (n=3598) and without (n=1884) K103N with susceptibility to etravirine by genotype was 77% and 49%, respectively. Among samples susceptible to first-generation NNRTIs (n=9458), >99% of samples were susceptible to etravirine by phenotype (FC <2.9); the remaining samples had FC ≥2.9-10. In summary, among samples submitted for routine clinical testing in the United States, a high proportion of samples with first-generation NNRTI resistance was susceptible to etravirine by genotype and phenotype. A higher proportion of NNRTI-resistant samples with K103N than without was susceptible to etravirine.
Gaston Picchio; Johan Vingerhoets; Lotke Tambuyzer; Eoin Coakley; Mojgan Haddad; James Witek


Response-guided telaprevir combination treatment for hepatitis C virus infection.
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Journal: The New England journal of medicineSeptember/26/2011
BACKGROUND
Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations.
METHODS
We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.
RESULTS
Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001).
CONCLUSIONS
In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809077/bin/nihms371976f1.jpg
Kenneth E Sherman; Steven L Flamm; Nezam H Afdhal; David R Nelson; Mark S Sulkowski; Gregory T Everson+11 authors

Viral particles with capside
Viral particles


Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial.

Journal: Lancet (London, England)Juli/28/2011
BACKGROUND
The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs).
METHODS
We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725.
RESULTS
From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001).
CONCLUSIONS
Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1.
BACKGROUND
Tibotec.
Calvin J Cohen; Jaime Andrade-Villanueva; Bonaventura Clotet; Jan Fourie; Margaret A Johnson; Kiat Ruxrungtham