A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Largely Improving the Output Performance of Stretchable Triboelectric Nanogenerators via Thermo-Compressive Technology.

Stretchable triboelectric nanogenerators (TENGs) are widely applied in wearable and implantable electronics, smart medical devices, and soft robots. However, it is still a challenge to produce stretchable TENGs with both exceptional elasticity and output performance, which limits their application scope. In this work, high-performance stretchable TENGs are developed through a thermo-compression (TC) fabrication process. In particular, a poly(vinylidene fluoride) film is compactly bound to the elastic thermoplastic polyurethane substrate, which inherits excellent stretchability with a strain of up to 815%. Furthermore, owing to the large surface area, tight contact, and effective vertical transport of tribo-induced charges between the coupled fibrous tribo-layer and soft substrate, the TC composite film-based TENGs exhibit a greater output (2-4 times) than unlaminated film-based TENGs. Additionally, the broad universality of this method is proven using various tribo- and substrate materials. The proposed technology provides a novel and effective approach to conjointly boost the output and stretchability of TENGs, showing encouraging application prospects in self-powered wearable and flexible electronics.

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

BACKGROUND: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19). METHODS: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale. RESULTS: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%). CONCLUSIONS: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Natural Antioxidant-Based Nanodrug for Atherosclerosis Treatment.

Natural antioxidants are always considered as candidates for the antioxidative therapy of atherosclerosis (AS) due to their good safety profile. However, restricted to their limited reactive oxygen species (ROS) elimination and rapid metabolism, the natural antioxidants' treatment suffers from the undesirable clinical outcomes. Herein, a new natural antioxidant-based nanodrug (VC@cLAVs) that can overcome above issues is developed to treat AS by loading natural antioxidant vitamin C (VC) into the natural antioxidant lipoic acid (LA)-constructed cross-linked vesicles. This integration not only greatly increases the blood half-life of natural antioxidants, but also amplifies the antioxidation capacity by the mutual recycling of two redox pairs LA/DHLA (reduced form of LA) and VC/DHA (oxidized form of VC). In vivo results disclose that VC@cLAVs decreases the apolipoprotein E-deficient mice's plaque area from 52% to 13%, much lower than those of free VC (≈45%) and LA (≈38%). This natural antioxidant-based nanodrug holds great potential in clinics.

Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials.

BACKGROUND: We sought to identify factors associated with weight gain in randomized clinical trials of antiretroviral therapy (ART) switch. METHODS: We explored the effects of demographic factors, clinical characteristics, and ART on weight gain in a pooled analysis of 12 prospective clinical trials, wherein virologically suppressed people living with human immunodeficiency virus (PWH) were randomized to switch or remain on a stable baseline regimen (SBR). RESULTS: Both PWH randomized to switch ART (n = 4166) and those remaining on SBR (n = 3150) gained weight. Median weight gain was greater in those who switched (1.6 kg, interquartile range [IQR], -.05 to 4.0 vs 0.4 kg, [IQR], -1.8 to 2.4 at 48 weeks, P < .0001), with most weight gain occurring in the first 24 weeks after switch. Among baseline demographic and clinical characteristics, only younger age and lower baseline body mass index were associated with any or ≥10% weight gain. By week 48, 4.6% gained ≥10% weight (6.4% of switch and 2.2% of SBR), the greatest risk was with switch from efavirenz (EFV) to rilpivirine (RPV) or elvitegravir/cobicistat and switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). Switch from abacavir to TAF was associated with less weight gain than switch from TDF to TAF and was not associated with increased risk for ≥10% weight gain. CONCLUSIONS: Moderate weight gain after ART switch was common and usually plateaued by 48 weeks. Baseline ART was a predictor of post-switch weight gain; participants who switched off of EFV and TDF had the greatest weight gain. The biological mechanisms that underlie the differential effects of switching ART agents on weight and associated clinical implications require further study.

Bimetallic-MOF-Derived Amorphous Zinc/Cobalt-Iron-Based Hollow Nanowall Arrays via Ion Exchange for Highly Efficient Oxygen Evolution.

Oxygen evolution reaction (OER) is critical for optimizing renewable energy systems, including metal-air batteries and water electrolysis. One major challenge for OER is to develop durable and cost-effective electrocatalysts with high catalytic performance. Herein, a controllable ion-exchange method to synthesize amorphous zinc/cobalt-iron hydroxide-based hollow nanowall arrays (A-Zn/Co-Fe HNAs) derived from bimetallic metal-organic frameworks (MOFs) on carbon cloth is reported. The amorphous characteristic enables the presented materials with more electrocatalytic sites and short diffusion paths for rapid access to the electrolyte, achieving efficient charge transfer for OER. The optimized nanostructure of A-Zn/Co-Fe HNAs via tuning the amount of iron sulfate in the reaction solution delivers a low overpotential of 226 mV to reach a current density of 10 mA cm-2 with a small Tafel slope of 37.81 mV dec-1 while exhibiting high durability at varied current densities over 80 h. The remarkable electrochemical performance can be attributed to the synergistic effect from chemical elements of Zn, Co-Fe, and a robust hollow structure. This simple method of fabricating bimetallic-MOF-derived amorphous Zn/Co-Fe HNAs on carbon cloth can be applied as a practical platform for other OER electrocatalysts.

Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials.

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. RESULTS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. CONCLUSIONS: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

Luteolin attenuates glucocorticoid-induced osteoporosis by regulating ERK/Lrp-5/GSK-3ß signaling pathway in vivo and in vitro.

Glucocorticoid-induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase-3, caspase-9, and Bax protein expressions and increased Bcl-2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt-related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal-regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3ß (GSK-3ß) phosphorylation, mRNA expression levels of lipoprotein-receptor-related protein 5 (Lrp-5) and ß-catenin. Further study revealed that Lrp-5 small interfering RNA (siRNA )and ERK-siRNA reduced the effects of LUT on GSK-3ß phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK-siRNA decreased Lrp-5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp-5/GSK-3ß pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks.

In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. METHODS: We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per µL, 50-199 cells per µL, or ≥200 cells per µL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0·6%, 95·002% CI -4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). INTERPRETATION: At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. FUNDING: Gilead Sciences.

Chitosan-based hydrogel dressings for diabetic wound healing via promoting M2 macrophage-polarization.

A long-term inflammatory phase of diabetic wounds is the primary cause to prevent their effective healing. Bacterial infection, excess reactive oxygen species (ROS), especially failure of M2-phenotype macrophage polarization can hinder the transition of diabetic wounds from an inflammation phase to a proliferation one. Herein, a chitosan-based hydrogel dressing with the ability of regulating M2 macrophage polarization was reported. The PAAc/CFCS-Vanillin hydrogel dressing was synthesized by one step thermal polymerization of catechol-functionalized chitosan (CFCS), acrylic acid, catechol functional methacryloyl chitosan­silver nanoparticles (CFMC-Ag NPs) and bioactive vanillin. The PAAc/CFCS-Vanillin hydrogel possessed sufficient mechanical strength and excellent adhesion properties, which helped rapidly block bleeding of wounds. Thanks to CFCS, CFMC-Ag NPs and vanillin in the hydrogel, it displayed excellent antibacterial infection in the wounds. Vanillin helped scavenge excess ROS and regulate the levels of inflammatory factors to facilitate the polarization of macrophages into the M2 phenotype. A full-thickness skin defect diabetic wound model showed that the wounds treated by the PAAc/CFCS-Vanillin hydrogel exhibited the smallest wound area, and superior granulation tissue regeneration, remarkable collagen deposition, and angiogenesis were observed in the wound tissue. Therefore, the PAAc/CFCS-Vanillin hydrogel could hold promising potential as a dressing for the treatment of diabetic chronic wounds.

The complete mitochondrial genome of a jujube geometrid, Sucra jujuba (Lepidoptera: Geometridae) and its phylogenetic analysis.

Sucra jujuba Chu, 1979 (Lepidoptera: Geometridae) is a major insect pest in jujube plantation. In this study, we have sequenced the complete mitochondrial genome of S. jujuba. The circular genome was 15,557 bp in length and contained 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and one AT-rich region (GenBank accession no. MZ507574). The nucleotide composition was significantly biased (A, T, C, and G were 41.85%, 39.65%, 10.97%, and 7.53%, respectively) with A + T contents of 81.50%. The Bayesian phylogenetic analysis of the concatenated nucleotide sequences of 13 PCGs from 30 species in the subfamily Ennominae and two outgroup species was performed. The results indicated that S. jujuba was closely related to Amraica recursaria in the subfamily Ennominae.

Viscoelastic blood coagulation testing system enabled by a non-contact triboelectric angle sensor.

Thromboelastography (TEG) remains a convenient and effective viscoelastic blood coagulation testing device for guiding blood component transfusion and assessing the risk of thrombosis. Here, a TEG enabled by a non-contact triboelectric angle sensor (NTAS) with a small size (∼7 cm3) is developed for assessing the blood coagulation system. With the assistance of a superelastic torsion wire structure, the NTAS-TEG realizes the detection of blood viscoelasticity. Benefiting from a grating and convex design, the NTAS holds a collection of compelling features, including accurate detection of rotation angles from -2.5° to 2.5°, high linearity (R 2 = 0.999), and a resolution of 0.01°. Besides, the NTAS exhibits merits of low cost and simplified fabrication. Based on the NTAS-TEG, a viscoelastic blood coagulation detection and analysis system is successfully constructed, which can provide a graph and parameters associated with clot initiation, formation, and stability for clinicians by using 0.36 mL of whole blood. The system not only validates the feasibility of the triboelectric coagulation testing sensor, but also further expands the application of triboelectric sensors in healthcare.

Establishment of Nested PCR for the Detection of Pseudomonas plecoglossicida and Epidemiological Survey of Larimichthys crocea in the Southeast Coastal Region.

The visceral white nodules disease in the internal organs of Larimichthys crocea has caused significant harm in the aquaculture of this species, with Pseudomonas plecoglossicida considered one of the core pathogens causing this disease. In this study, we designed three pairs of specific nested PCR primers targeting the sctU gene of P. plecoglossicida, a crucial component of the Type III secretion system (T3SS), which is instrumental in bacterial pathogenesis and virulence. Through the optimization of PCR reaction conditions, specificity testing, and sensitivity determination, a method was established for the accurate detection of P. plecoglossicida. This method yielded single amplification products, exhibited a false positive rate of zero for reference bacteria, and achieved a detection sensitivity of a minimum of 2.62 copies/reaction for the target sequence. Using the detection method, we conducted analyses on the diseased populations of L. crocea, involving a total of 64 screened fishes along the southeast coast of China from 2021 to 2023. The results revealed that the infection rate of P. plecoglossicida in diseased L. crocea exceeded over 90% in March and April, while in other months, the maximum recorded infection rate was merely 10%. The detection method developed in this study shows potential for early warning and routine monitoring of visceral white nodules disease in the internal organs of species such as L. crocea.

Unraveling Ros Conversion Through Enhanced Enzyme-Like Activity with Copper-Doped Cerium Oxide for Tumor Nanocatalytic Therapy.

Nanozyme catalytic therapy for cancer treatments has become one of the heated topics, and the therapeutic efficacy is highly correlated with their catalytic efficiency. In this work, three copper-doped CeO2 supports with various structures as well as crystal facets are developed to realize dual enzyme-mimic catalytic activities, that is superoxide dismutase (SOD) to reduce superoxide radicals to H2 O2 and peroxidase (POD) to transform H2 O2 to ∙OH. The wire-shaped CeO2 /Cu-W has the richest surface oxygen vacancies, and a low level of oxygen vacancy (Vo) formation energy, which allows for the elimination of intracellular reactive oxygen spieces (ROS) and continuous transformation to ∙OH with cascade reaction. Moreover, the wire-shaped CeO2 /Cu-W displays the highest toxic ∙OH production capacity in an acidic intracellular environment, inducing breast cancer cell death and pro-apoptotic autophagy. Therefore, wire-shaped CeO2 /Cu nanoparticles as an artificial enzyme system can have great potential in the intervention of intracellular ROS in cancer cells, achieving efficacious nanocatalytic therapy.

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial.

BACKGROUND: The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. METHODS: This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. FINDINGS: 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI -1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 µmol/L vs 260 µmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 µmol/L vs 7 µmol/L). INTERPRETATION: If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. FUNDING: Gilead Sciences.

Exploring the within- and between-class correlation distributions for tumor classification.

To many biomedical researchers, effective tumor classification methods such as the support vector machine often appear like a black box not only because the procedures are complex but also because the required specifications, such as the choice of a kernel function, suffer from a clear guidance either mathematically or biologically. As commonly observed, samples within the same tumor class tend to be more similar in gene expression than samples from different tumor classes. But can this well-received observation lead to a useful procedure of classification and prediction? To address this issue, we first conceived a statistical framework and derived general conditions to serve as the theoretical foundation that supported the aforementioned empirical observation. Then we constructed a classification procedure that fully utilized the information obtained by comparing the distributions of within-class correlations with between-class correlations via Kullback-Leibler divergence. We compared our approach with many machine-learning techniques by applying to 22 binary- and multiclass gene-expression datasets involving human cancers. The results showed that our method performed as efficiently as support vector machine and Naïve Bayesian and outperformed other learning methods (decision trees, linear discriminate analysis, and k-nearest neighbor). In addition, we conducted a simulation study and showed that our method would be more effective if the arriving new samples are subject to the often-encountered baseline shift or increased noise level problems. Our method can be extended for general classification problems when only the similarity scores between samples are available.

Genetic Diversity and Structure Revealed by Genomic Microsatellite Markers of Mytilus unguiculatus in the Coast of China Sea.

The hard-shelled mussel Mytilus unguiculatus plays an important role in mussel aquaculture in China due to its characteristic and nutritive value. In this study, 10 microsatellite loci are used to study the genetic diversity and genetic structure of seven location populations of M. unguiculatus in coastal areas of China. The results of amplification and genotyping show that the observed heterozygosity (Ho) and the expected heterozygosity (He) are 0.61~0.71 and 0.72~0.83, respectively. M. unguiculatus has high genetic diversity. The inbreeding index (FIS) of M. unguiculatus is significantly positive (FIS: 0.14~0.19), indicating that inbreeding might exist within populations. The genetic structure of M. unguiculatus is weak within populations from the East China Sea All results showed that genetic differences existed between the Qingdao population from the Yellow Sea and other populations from the East China Sea. It does not detect a population bottleneck event or expansion event in the populations. The results from this study can be used to provide important insights in genetic management units and sustainable utilization of M. unguiculatus resources and provide a better understand of genetic structure of marine bivalve with similar planktonic larval stage in the China Sea.

Intermediates Regulation via Electron-Deficient Cu Sites for Selective Nitrate-to-Ammonia Electroreduction.

Ammonia (NH3 ), known as one of the fundamental raw materials for manufacturing commodities such as chemical fertilizers, dyes, ammunitions, pharmaceuticals, and textiles, exhibits a high hydrogen storage capacity of ≈17.75%. Electrochemical nitrate reduction (NO3 RR) to valuable ammonia at ambient conditions is a promising strategy to facilitate the artificial nitrogen cycle. Herein, copper-doped cobalt selenide nanosheets with selenium vacancies are reported as a robust and highly efficient electrocatalyst for the reduction of nitrate to ammonia, exhibiting a maximum Faradaic efficiency of ≈93.5% and an ammonia yield rate of 2360 µg h-1 cm-2 at -0.60 V versus reversible hydrogen electrode. The in situ spectroscopical and theoretical study demonstrates that the incorporation of Cu dopants and Se vacancies into cobalt selenide efficiently enhances the electron transfer from Cu to Co atoms via the bridging Se atoms, forming the electron-deficient structure at Cu sites to accelerate NO3 - dissociation and stabilize the *NO2 intermediates, eventually achieving selective catalysis in the entire NO3 RR process to produce ammonia efficiently.

Dual-sensory fusion self-powered triboelectric taste-sensing system towards effective and low-cost liquid identification.

Infusing human taste perception into smart sensing devices to mimic the processing ability of gustatory organs to perceive liquid substances remains challenging. Here we developed a self-powered droplet-tasting sensor system based on the dynamic morphological changes of droplets and liquid-solid contact electrification. The sensor system has achieved accuracies of liquid recognition higher than 90% in five different applications by combining triboelectric fingerprint signals and deep learning. Furthermore, an image sensor is integrated to extract the visual features of liquids, and the recognition capability of the liquid-sensing system is improved to up to 96.0%. The design of this dual-sensory fusion self-powered liquid-sensing system, along with the droplet-tasting sensor that can autonomously generate triboelectric signals, provides a promising technological approach for the development of effective and low-cost liquid sensing for liquid food safety identification and management.