Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration ...and as a long-acting injectable suspension (long-acting CAB CAB LA) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.
HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population.
In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress.
ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.
Two-dimensional covalent organic frameworks (2D COFs) are crystalline polymer networks whose modular 2D structures and permanent porosity motivate efforts to integrate them into sensing, energy ...storage, and optoelectronic devices. These applications require forming the material as a thin film instead of a microcrystalline powder, which has been achieved previously by including a substrate in the reaction mixture. This approach suffers from two key drawbacks: COF precipitates form concurrently and contaminate the film, and variable monomer and oligomer concentrations during the polymerization provide poor control over film thickness. Here we address these challenges by growing 2D COF thin films under continuous flow conditions. Initially homogeneous monomer solutions polymerize while pumped through heated tubing for a given residence time, after which they pass over a substrate. When the residence time and conditions are chosen judiciously, 2D COF powders form downstream of the substrate, and the chemical composition of the solution at the substrate remains constant. COF films grown in flow exhibit constant rates of mass deposition, enabling thickness control as well as access to thicker films than are available from previous static growth procedures. Notably, the crystallinity of COF films is observed only at longer residence times, suggesting that oligomeric and polymeric species play an important role in forming the 2D COF lattice. This approach, which we demonstrate for four different frameworks, is both a simple and powerful method to control the formation of COF thin films.
We present high-resolution ALMA Band 6 and 7 observations of the tidally disrupted protoplanetary disks of the RW Aurigae binary. Our observations reveal tidal streams in addition to the previously ...observed tidal arm around RW Aur A. The observed configuration of tidal streams surrounding RW Aur A and B is incompatible with a single star-disk tidal encounter, suggesting that the RW Aurigae system has undergone multiple flyby interactions. We also resolve the circumstellar disks around RW Aur A and B, with CO radii of 58 au and 38 au consistent with tidal truncation, and 2.5 times smaller dust emission radii. The disks appear misaligned by 12° or 57°. Using new photometric observations from the American Association of Variable Star Observers (AAVSO) and the All Sky Automated Survey for SuperNovae (ASAS-SN) archives, we have also identified an additional dimming event of the primary that began in late 2017 and is currently ongoing. With over a century of photometric observations, we are beginning to explore the same spatial scales as ALMA.
Abstract Background Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR ...gene targets. Objective To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). Design, setting, and participants We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen PSA ≥8 ng/ml or PSA doubling time PSA DT ≤10 mo). Intervention Patients received 240 mg/d apalutamide while continuing on androgen-deprivation therapy. Outcome measurements and statistical analysis Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). Results and limitations A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval CI, 16.3 mo–not reached NR); median MFS was NR (95% CI, 33.4 mo–NR). Most of the patients discontinued study treatment ( n = 33) due to disease progression ( n = 11 22%) or adverse events (AEs) ( n = 9 18%). The most common AE was fatigue (any grade, n = 31 61%) although grade ≥3 fatigue was uncommon ( n = 2 4%). These represent the first apalutamide nmCRPC patient clinical data. Conclusions In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. Patient summary Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. Trial registration ClinicalTrials.gov identifier NCT01171898
The HIV envelope (Env) protein gpl20 is protected from antibody recognition by a dense glycan shield. However, several of the recently identified PGT broadly neutralizing antibodies appear to ...interact directly with the HIV glycan coat. Crystal structures of antigen-binding fragments (Fabs) PGT 127 and 128 with Man 9 at 1.65 and 1.29 angstrom resolution, respectively, and glycan binding data delineate a specific high mannose-binding site. Fab PGT 128 complexed with a fully g ly cosy la ted gpl20 outer domain at 3.25 angstroms reveals that the antibody penetrates the glycan shield and recognizes two conserved glycans as well as a short ß-strand segment of the gpl20 V3 loop, accounting for its high binding affinity and broad specificify. Furthermore, our data suggest that the high neutralization potency of PGT 127 and 128 immunoglobulin Gs may be mediated by cross-linking Env trimers on the viral surface.
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their ...abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
Objective
Treatment for opioid use disorder (OUD) may include a combination of pharmacotherapies (such as buprenorphine) with counseling services if clinically indicated. Medication management or ...engagement with in-person counseling services may be hindered by logistical and financial barriers. Telehealth may provide an alternative mechanism for continued engagement. This study aimed to evaluate the association between telehealth encounters and time to discontinuation of buprenorphine treatment when compared to traditional in-person visits and to evaluate potential effect modification by rural-urban designation and in-person and telehealth combination treatment.
Methods
A retrospective cohort study of Veterans diagnosed with OUD and treated with buprenorphine across all facilities within the Veterans Health Administration (VHA) between 2008 and 2017. Exposures were telehealth and in-person encounters for substance use disorder (SUD) and mental health, treated as time-varying covariates. The primary outcome was treatment discontinuation, evaluated as 14 days of absence of medication from initiation through 1 year.
Results
Compared to in-person encounters, treatment discontinuation was lower for telehealth for SUD (aHR: 0.69; 95%CI: 0.60, 0.78) and mental health (aHR: 0.69; 95%CI: 0.62, 0.76). There was no evidence of effect modification by rural-urban designation. Risk of treatment discontinuation appeared to be lower among those with telehealth only compared to in-person only for both SUD (aHR: 0.48, 95%CI: 0.37, 0.62) and for mental health (aHR: 0.46; 95%CI: 0.33, 0.65).
Conclusions
As telehealth demonstrated improved treatment retention compared to in-person visits, it may be a suitable option for engagement for patients in OUD management. Efforts to expand services may improve treatment retention and health outcomes for VHA and other health care systems.
Purpose
Regional anesthesia has been shown to improve outcomes in several recent studies. The transversus abdominis plane (TAP) block provides anesthesia to the abdominal wall by introducing local ...anesthetic to the ventral rami of the thoracolumbar nerves. This work quantifies the area of anesthesia obtained after performing the novel thoracolumbar interfascial plane block (analogous to the TAP block but intended for the back) which targets the sensory component of the dorsal rami of the thoracolumbar nerves.
Methods
Ten participants underwent bilateral ultrasound-guided injections of 0.2% ropivacaine 20 mL into the fascial plane between the multifidus and longissimus muscles. After five and 20 min, respectively, the area of anesthesia was plotted on the participant’s back. Anesthesia was defined as loss of point discrimination to pinprick.
Results
Participants reported a mean (SD) area of anesthesia surrounding the needle injection site of 137.4 (71.0) cm
2
and 217.0 (84.7) cm
2
at five and 20 min after injection, respectively. The mean (SD) cephalad and caudal spread of local anesthetic from the site of injection was 6.5 (1.8) cm and 3.9 (1.2) cm, respectively. There were no complications or adverse events reported.
Conclusion
This report shows that a reproducible area of anesthesia can be obtained by ultrasound-guided injection of local anesthetic in the fascial plane between the multifidus and longissimus muscles of the thoracolumbar spine. The area of anesthesia consistently covered the midline and had a predictable spread. This project was registered with clinicaltrials.gov (NCT02297191).
We present results on the dust attenuation curve of z, ~ 2 galaxies using early observations from the MOSFIRE Deep Evolution Field survey. Our sample consists of 224 star-forming galaxies with z ...sub(spec) = 1.36-2.59 and high signal-to-noise ratio measurements of H alpha and H beta obtained with Keck/MOSFIRE. We construct composite spectral energy distributions (SEDs) of galaxies in bins of Balmer decrement to measure the attenuation curve. We find a curve that is similar to the SMC extinction curve at lambda gap 2500 A. At shorter wavelengths, the shape is identical to that of the Calzetti et al. relation, but with a lower normalization. Hence, the new attenuation curve results in star formation rates (SFRs) that are approximately 20% lower, and stellar masses that are Delta log(M super(*)/M sub(middot in circle))Asymptotically = to 0.16 dex lower, than those obtained with the Calzetti relation. We find that the difference in the total attenuation of the ionized gas and stellar continuum correlates strongly with SFR, such that for dust-corrected SFRs gap 20 M sub(middot in circle) yr super(-1), assuming a Chabrier initial mass function, the nebular emission lines suffer an increasing degree of obscuration relative to the continuum. A simple model that can account for these trends is one in which the UV through optical stellar continuum is dominated by a population of less-reddened stars, while the nebular line and bolometric luminosities become increasingly dominated by dustier stellar populations for galaxies with large SFRs, as a result of the increased dust enrichment that accompanies such galaxies. Consequently, UV- and SED-based SFRs may underestimate the total SFR at even modest levels of approximately 20 M sub(middot in circle)yr super(-1).
Objective
To define symptomatology and responses to treatment in chronic sialadenitis from sialolithiasis versus duct stenosis and establish a minimal clinically significant difference (MCID) in the ...validated Obstructive Salivary Problem Impact Test (SPIT).
Study Design
Prospective, cohort.
Setting
Tertiary‐care center.
Methods
Patients completed the SPIT questionnaire at presentation and 3 to 6 months after surgery. SPIT scores and domains were compared between patients with symptomatic sialolithiasis and those with stenosis of a major salivary gland.
Results
Seventy‐nine patients completed the SPIT, including 43 (54%) with sialolithiasis and 36 (46%) with stenosis. Stenosis patients displayed greater baseline scores compared to sialolithiasis patients (45.4 ± 19.9 vs 33.3 ± 18.5, P < .013). Frequency and severity of gland swelling and pain (21.9 ± 8.9 vs 17.1 ± 9.6, P = .02) and functional/psychosocial impact subscores were greater in the stenosis versus sialolithiasis groups (18.0 ± 10.9 vs 11.3 ± 9.4, P < .01). For 43 patients who underwent surgical intervention, SPIT scores improved at 3 to 6 months postoperatively in all domains (−18.6 ± 19.4, P < .01). Degree of improvement did not differ between sialolithiasis versus stenosis groups (−22.0 ± 20.9 vs −13.3 ± 15.8, P = .13). The MCID in SPIT score was found to be −13 points. A postoperative SPIT score of less than 10 suggested symptom resolution.
Conclusion
When compared to sialolithiasis, chronic salivary obstruction from stenosis is associated with greater baseline SPIT scores, indicating poorer sialadenitis‐related quality of life due to greater symptom frequency and functional impact. Based on SPIT survey outcomes, a score decrease of 13 points or SPIT score <10 represent significant symptom improvement.
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