Week 96 Extension Results of a Phase 3 Study Evaluating Long-Acting Cabotegravir with Rilpivirine for HIV-1 Treatment

BACKGROUND: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented. METHODS AND DESIGN: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes. RESULTS: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27). CONCLUSION: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1

Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption

Long-acting injectable Cabotegravir + Rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression

Amplified and directional spontaneous emission from arbitrary composite bodies: A self-consistent treatment of Purcell effect below threshold

We study amplified spontaneous emission (ASE) from wavelength-scale composite bodies - complicated arrangements of active and passive media - demonstrating highly directional and tunable radiation patterns, depending strongly on pump conditions, materials, and object shapes. For instance, we show that under large enough gain, PT symmetric dielectric spheres radiate mostly along either active or passive regions, depending on the gain distribution. Our predictions are based on a recently proposed fluctuating-volume-current formulation of electromagnetic radiation that can handle inhomogeneities in the dielectric and fluctuation statistics of active media, e.g., arising from the presence of nonuniform pump or material properties, which we exploit to demonstrate an approach to modeling ASE in regimes where Purcell effect (PE) has a significant impact on the gain, leading to spatial dispersion and/or changes in power requirements. The nonlinear feedback of PE on the active medium, captured by the Maxwell-Bloch equations but often ignored in linear formulations of ASE, is introduced into our linear framework by a self-consistent renormalization of the (dressed) gain parameters, requiring the solution of a large system of nonlinear equations involving many linear scattering calculations

Initial evaluation of the Robert Wood Johnson Foundation Nurse Faculty Scholars program

BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars (RWJF NFS) program was developed to enhance the career trajectory of young nursing faculty and to train the next generation of nurse scholars. Although there are publications that describe the RWJF NFS, no evaluative reports have been published. The purpose of this study was to evaluate the first three cohorts (n = 42 scholars) of the RWJF NFS program. METHODS: A descriptive research design was used. Data were derived from quarterly and annual reports, and a questionnaire (seven open-ended questions) was administered via Survey Monkey Inc. (Palo Alto, CA, USA). RESULTS: During their tenure, scholars had on average six to seven articles published, were teaching/mentoring at the graduate level (93%), and holding leadership positions at their academic institutions (100%). Eleven scholars (26%) achieved fellowship in the American Academy of Nursing, one of the highest nursing honors. The average ratings on a Likert scale of 1 (not at all supportive) to 10 (extremely supportive) of whether or not RWJF had helped scholars achieve their goals in teaching, service, research, and leadership were 7.7, 8.0, 9.4, and 9.5, respectively. The majority of scholars reported a positive, supportive relationship with their primary nursing and research mentors; although, several scholars noted challenges in connecting for meetings or telephone calls with their national nursing mentors. CONCLUSIONS: These initial results of the RWJF NFS program highlight the success of the program in meeting its overall goal—preparing the next generation of nursing academic scholars for leadership in the profession

Desirability Functions in Multiresponse Optimization

Desirability functions (DFs) play an increasing role for solving the optimization of process or product quality problems having various quality characteristics to obtain a good compromise between these characteristics. There are many alternative formulations to these functions and solution strategies suggested for handling their weaknesses and improving their strength. Although the DFs of Derringer and Suich are the most popular ones in multiple-response optimization literature, there is a limited number of solution strategies to their optimization which need to be updated with new research results obtained in the area of nonlinear optimization