Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and ...rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study.
We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2).
We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0·2% (95% CI −3·0 to 2·5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 10% for dolutegravir-rilpivirine vs 50 10% for CAR) and headache (41 8% vs 23 5%). More participants taking dolutegravir-rilpivirine (17 3%) reported adverse events leading to withdrawal than did participants taking CAR (three <1%).
Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression.
ViiV Healthcare and Janssen Pharmaceutica NV.
There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we ...conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10
), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10
) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10
), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10
). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.
Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from ...inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2
Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.
Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of ...macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.
Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that ...treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs.
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•MGAT2 inhibitor BMS-963272 decreased inflammation and fibrosis in murine NASH models•BMS-963272 increased PYY and FGF-21 and decreased body weight in human subjects•Elevation of long-chain DCAs is a specific PD biomarker for MGAT2 inhibitors•MGAT2 inhibition is a promising approach for the treatment of NASH
Cheng et al. demonstrate that MGAT2 inhibitor BMS-963272 decreased inflammation and fibrosis in CDAHFD and STAM mice and body weight in human obese subjects, which is consistent with elevation of gut hormone PYY and GLP-1 levels. Long-chain DCAs can serve as a specific translational PD biomarker for MGAT2 inhibitors.
Combined analyses of deep tow magnetic anomalies and International Ocean Discovery Program Expedition 349 cores show that initial seafloor spreading started around 33 Ma in the northeastern South ...China Sea (SCS), but varied slightly by 1–2 Myr along the northern continent‐ocean boundary (COB). A southward ridge jump of ∼20 km occurred around 23.6 Ma in the East Subbasin; this timing also slightly varied along the ridge and was coeval to the onset of seafloor spreading in the Southwest Subbasin, which propagated for about 400 km southwestward from ∼23.6 to ∼21.5 Ma. The terminal age of seafloor spreading is ∼15 Ma in the East Subbasin and ∼16 Ma in the Southwest Subbasin. The full spreading rate in the East Subbasin varied largely from ∼20 to ∼80 km/Myr, but mostly decreased with time except for the period between ∼26.0 Ma and the ridge jump (∼23.6 Ma), within which the rate was the fastest at ∼70 km/Myr on average. The spreading rates are not correlated, in most cases, to magnetic anomaly amplitudes that reflect basement magnetization contrasts. Shipboard magnetic measurements reveal at least one magnetic reversal in the top 100 m of basaltic layers, in addition to large vertical intensity variations. These complexities are caused by late‐stage lava flows that are magnetized in a different polarity from the primary basaltic layer emplaced during the main phase of crustal accretion. Deep tow magnetic modeling also reveals this smearing in basement magnetizations by incorporating a contamination coefficient of 0.5, which partly alleviates the problem of assuming a magnetic blocking model of constant thickness and uniform magnetization. The primary contribution to magnetic anomalies of the SCS is not in the top 100 m of the igneous basement.
Key Points:
Deep tow magnetics and IODP Expedition 349 constrained opening history
Variations are observed in spreading rate and onset of drifting and ridge jump
Magnetic anomalies are not primarily sourced from the top 100 m of the basement
Abstract
Background
There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL ...risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown.
Methods
We performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB–mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.
Results
We identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10–45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10–22 and 2.1 × 10–18, respectively).
Conclusions
Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.
C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using ...newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
BACKGROUND AND PURPOSE—Recently, the Mobile Stroke Unit (MSU) concept was introduced in Germany demonstrating prehospital treatment of more patients within the first hour of symptom onset. However, ...the details and complexities of establishing such a program in the United States are unknown. We describe the steps involved in setting up the first MSU in the United States.
METHODS—Implementation included establishing leadership, fund-raising, purchase and build-out, knitting a collaborative consortium of community stakeholders, writing protocols to ensure accountability, radiation safety, purchasing supplies, licensing, insurance, establishing a base station, developing a communication plan with city Emergency Medical Services, Emergency Medical Service training, staffing, and designing a research protocol.
RESULTS—The MSU was introduced after ≈1 year of preparation. Major obstacles to establishing the MSU were primarily obtaining funding, licensure, documenting radiation safety protocols, and establishing a smooth communication system with Emergency Medical Services. During an 8 week run-in phase, ≈2 patients were treated with recombinant tissue-type plasminogen activator per week, one-third within 60 minutes of symptom onset, with no complications. A randomized study to determine clinical outcomes, telemedicine reliability and accuracy, and cost effectiveness was formulated and has begun.
CONCLUSION—The first MSU in the United States has been introduced in Houston, TX. The steps needed to accomplish this are described.
Expanding indications for cardiovascular implantable electronic devices are accompanied by an increasing burden of device clinic follow-up. Remote monitoring (RM) may be less time-consuming compared ...to in-office follow-up; however, its effect on the device clinic workflow has not been clarified.
To determine the impact of RM on device clinic workflow.
Detailed workflow data were prospectively collected over a 2-week period in a busy device clinic.
Five hundred remote transmissions were received from 434 patients between March 1 and March 16, 2011--346 implantable cardioverter-defibrillator, 84 pacemaker, and 70 implantable loop recorder transmissions--on 4 RM platforms (CareLink 56.4%, Merlin.net 21.4%, LATITUDE 17.8%, and Home Monitoring 4.4%). The mean time spent per transmission was 11.5 ± 7.7 minutes, which was less than in-person interrogations (27.7 ± 9.9 minutes; P <.01). Of 500 transmissions, 135 (27.0%) demonstrated clinically important findings; however, only 41 (8.2%) were forwarded for physician review. Of 500 transmissions, 138 (27.6%) were unscheduled, and these were more likely to contain a clinically important event (56 of 138 40.6% vs 79 of 362 21.8%; P = .0001). A total of 5.8% of the transmissions were duplicate. Transmissions that revealed clinically important findings took longer to process than those that did not (21.0 ± 7.4 minutes vs 10.1 ± 2.1 minutes; P <.05). A total of 49.2% of the scheduled remote transmissions were missed because of patient noncompliance. Telephone follow-up of patients (mean 21 patients/d) who missed scheduled remote transmissions took a mean of 55.1 (range 20-98) min/d.
Analysis of RM transmissions has significant implications for the device clinic workflow. Nonactionable transmissions are rapidly processed, allowing clinicians to focus on clinically important findings. However, poor patient compliance complicates the workflow efficiency of currently available systems.
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