Graphene Oxide-Poly(vinyl alcohol) Hydrogel-Coated Solid-Contact Ion-Selective Electrodes for Wearable Sweat Potassium Ion Sensing.

Solid-contact ion-selective electrodes (SC-ISEs) with ionophore-based polymer-sensitive membranes have been the major devices in wearable sweat sensors toward electrolyte analysis. However, the toxicity of ionophores in ion-selective membranes (ISMs), for example, valinomycin (K+ ion carrier), is a significant challenge, since the ISM directly contacts the skin during the tests. Herein, we report coating a hydrogel of graphene oxide-poly(vinyl alcohol) (GO-PVA) on the ISM to fabricate hydrogel-based SC-ISEs. The hydrogen bond interaction between GO sheets and PVA chains could enhance the mechanical strength through the formation of a cross-linking network. Comprehensive electrochemical tests have demonstrated that hydrogel-coated K+-SC-ISE maintains Nernstian response sensitivity, high selectivity, and anti-interference ability compared with uncoated K+-SC-ISE. A flexible hydrogel-based K+ sensing device was further fabricated with the integration of a solid-contact reference electrode, which has realized the monitoring of sweat K+ in real time. This work highlights the possibility of hydrogel coating for fabricating biocompatible wearable potentiometric sweat electrolyte sensors.

Associating Knee Osteoarthritis Progression with Temporal-Regional Graph Convolutional Network Analysis on MR Images.

BACKGROUND: Artificial intelligence shows promise in assessing knee osteoarthritis (OA) progression on MR images, but faces challenges in accuracy and interpretability. PURPOSE: To introduce a temporal-regional graph convolutional network (TRGCN) on MR images to study the association between knee OA progression status and network outcome. STUDY TYPE: Retrospective. POPULATION: 194 OA progressors (mean age, 62 ± 9 years) and 406 controls (mean age, 61 ± 9 years) from the OA Initiative were randomly divided into training (80%) and testing (20%) cohorts. FIELD STRENGTH/SEQUENCE: Sagittal 2D IW-TSE-FS (IW) and 3D-DESS-WE (DESS) at 3T. ASSESSMENT: Anatomical subregions of cartilage, subchondral bone, meniscus, and the infrapatellar fat pad at baseline, 12-month, and 24-month were automatically segmented and served as inputs to form compartment-based graphs for a TRGCN model, which containing both regional and temporal information. The performance of models based on (i) clinical variables alone, (ii) radiologist score alone, (iii) combined features (containing i and ii), (iv) composite TRGCN (combining TRGCN, i and ii), (v) radiomics features, (vi) convolutional neural network based on Densenet-169 were compared. STATISTICAL TESTS: DeLong test was performed to compare the areas under the ROC curve (AUC) of all models. Additionally, interpretability analysis was done to evaluate the contributions of individual regions. A P value <0.05 was considered significant. RESULTS: The composite TRGCN outperformed all other models with AUCs of 0.841 (DESS) and 0.856 (IW) in the testing cohort (all P < 0.05). Interpretability analysis highlighted cartilage's importance over other structures (42%-45%), tibiofemoral joint's (TFJ) dominance over patellofemoral joint (PFJ) (58%-67% vs. 12%-37%), and importance scores changes in compartments over time (TFJ vs. PFJ: baseline: 44% vs. 43%, 12-month: 52% vs. 39%, 24-month: 31% vs. 48%). DATA CONCLUSION: The composite TRGCN, capturing temporal and regional information, demonstrated superior discriminative ability compared with other methods, providing interpretable insights for identifying knee OA progression. TECHNICAL EFFICACY: Stage 2.

Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19.

BACKGROUND: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life. OBJECTIVE: To assess the safety and efficacy of amubarvimab plus romlusevimab. DESIGN: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410). SETTING: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines. PATIENTS: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression. INTERVENTION: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo. MEASUREMENTS: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death. RESULTS: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events. LIMITATION: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants. CONCLUSION: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Beyond Nonactin: Potentiometric Ammonium Ion Sensing Based on Ion-selective Membrane-free Prussian Blue Analogue Transducers.

The determination of ammonium ions (NH4+) is of significance to environmental, agriculture, and human health. Potentiometric NH4+ sensors based on solid-contact ion selective electrodes (SC-ISEs) feature point-of-care testing and miniaturization. However, the state-of-the-art SC-ISEs of NH4+ during the past 20 years strongly rely on the organic ammonium ionophore-based ion selective membrane (ISM), typically by nonactin for the NH4+ recognition. Herein, we report a Prussian blue analogue of copper(II)-hexacyanoferrate (CuHCF) for an ISM-free potentiometric NH4+ sensor without using the ionophores. CuHCF works as a bifunctional transducer that could realize the ion-to-electron transduction and NH4+ recognition. CuHCF exhibits competitive analytical performances regarding traditional nonactin-based SC-ISEs of NH4+, particularly for the selectivity toward K+. The cost and preparation process have been remarkably reduced. The theoretical calculation combined with electrochemical tests further demonstrate that relatively easier intercalation of NH4+ into the lattices of CuHCF determines its selectivity. This work provides a concept of the ISM-free potentiometric NH4+ sensor beyond the nonactin ionophore through a CuHCF bifunctional transducer.

Quantitative MR evaluation of the infrapatellar fat pad for knee osteoarthritis: using proton density fat fraction and T2* relaxation based on DIXON.

OBJECTIVES: To investigate the efficacy of fat fraction (FF) and T2* relaxation based on DIXON in the assessment of infrapatellar fat pad (IFP) for knee osteoarthritis (KOA) progression in older adults. METHODS: Ninety volunteers (age range 51-70 years, 65 females) were enrolled in this study. Participants were grouped based on the Kellgren-Lawrence grading (KLG). The FF and T2* values were measured based on the 3D-modified DXION technique. Cartilage defects, bone marrow lesions, and synovitis were assessed based on a modified version of whole-organ magnetic resonance imaging score (WORMS). Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaire. The differences of FF and T2* measurement and the correlation with WORMS and WOMAC assessments were analyzed. Diagnostic efficiency was analyzed by using receiver operating characteristic (ROC) curves. RESULTS: A total of 60 knees were finally included (n = 20 in each group). The values were 82.6 ± 3.7%, 74.7 ± 5.4%, and 60.5 ± 14.1% for FF is the no OA, mild OA, and advanced OA groups, and were 50.7 ± 6.6 ms, 44.1 ± 6.6 ms, and 39.1 ± 4.2 ms for T2*, respectively (all p values < 0.001). The WORMS assessment and WOMAC pain assessment showed negative correlation with FF and T2* values. The ROC showed the area under the curve (AUC), sensitivity, and specificity for diagnosing OA were 0.93, 77.5%, and 100% using FF, and were 0.86, 75.0%, and 90.0% using T2*, respectively. CONCLUSIONS: FF and T2* alternations in IFP are associated with knee structural abnormalities and clinical symptoms cross-sectionally and may have the potential to predict the severity of KOA. KEY POINTS: • Fat fraction (FF) and T2* relaxation based on DIXON imaging are novel methods to quantitatively assess the infrapatellar fat pad for knee osteoarthritis (KOA) progression in older adults. • The alterations of FF and T2* using mDIXON technique in IFP were associated with knee structural abnormalities and clinical symptoms. • FF and T2* alternations in IFP can serve as the new imaging biomarkers for fast, simple, and noninvasive assessment in KOA.

Synergistic engineering of shell thickness and core ordering to boost the oxygen reduction performance.

When benchmarked against the extended Pt(111), slightly weaker adsorption and stronger cohesion properties of surface Pt are required to improve activity and durability for the oxygen reduction reaction, respectively, making it challenging to meet both requirements on one surface. Here, using Pt(111) over-layers stressed and modified by Pt-TM (TM = Fe, Co, Ni, V, Cu, Ag, and Pd) intermetallics as examples, we theoretically identified ten promising catalysts by synergistically tailoring the skin thickness and substrate chemical ordering to simultaneously achieve weak adsorption and strong cohesion. More specifically, compared with Pt(111), all candidates exhibit 10-fold enhanced activity, half of which show improved durability, such as mono-layer skin on L12-Pt3Co or Pt3Fe, double-layer Pt on L13-Pt3Ni or Pt3Cu, and triple-layer skin on L11-PtCu, while double- or triple-layer skin on L10-PtCo or PtNi and double-layer skin on L12-PtFe3 show slightly poor durability. Although L10 and L12 based nanocrystals have been demonstrated extensively as outstanding catalysts, L11 and L13 ones hold great application potential. The coexistence of high activity and durability on the same surface is because of the different responses of surface adsorption and cohesion properties to the strain effects and ligand effects. When intermetallic-core@Pt-shell nanocrystals are constructed using this slab model, the necessity of protecting or eliminating low-coordinated Pt and the possibility of maximizing Pt(111) facets and core ordering by morphology engineering were highlighted. The current discovery provides a new paradigm toward the rational design of promising cathodic catalysts.

Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care.

BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. CLINICAL TRIALS REGISTRATION: NCT04292899 and EUPAS34303.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.

Solid-Contact Ion Sensing Without Using an Ion-Selective Membrane through Classic Li-Ion Battery Materials.

The solid-contact ion-selective electrodes (SC-ISEs) are a type of potentiometric analytical device with features of rapid response, online analysis, and miniaturization. The state-of-the-art SC-ISEs are composed of a solid-contact (SC) layer and an ion-selective membrane (ISM) layer with respective functions of ion-to-electron transduction and ion recognition. Two challenges for the SC-ISEs are the water-layer formation at the SC/ISM phase boundary and the leaking of ISM components, which are both originated from the ISM. Herein, we report a type of SC-ISE based on classic Li-ion battery materials as the SC layer without using the ISM for potentiometric lithium-ion sensing. Both LiFePO4- and LiMn2O4-based SC-ISEs display good Li+ sensing properties (sensitivity, selectivity, and stability). The proposed LiFePO4 electrode exhibits comparable sensitivity and a linear range to conventional SC-ISEs with ISM. Owing to the nonexistence of ISM, the LiFePO4 electrode displays high potential stability. Besides, the LiMn2O4 electrode shows a Nernstian response toward Li+ sensing in a human blood serum solution. This work emphasizes the concept of non-ISM-based SC-ISEs for potentiometric ion sensing.

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.

Concordance of HIV-1 RNA Values by Amplicor and TaqMan 2.0 in Patients With Confirmed Suppression in Clinical Trials.

BACKGROUND: The COBAS AMPLICOR HIV-1 MONITOR Test, version 1.5 (Amplicor) has been replaced with the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 (TaqMan 2.0), a real-time polymerase chain reaction human immunodeficiency virus type 1 (HIV-1) assay with higher sensitivity and broader dynamic range. HIV-1 RNA values at the 50 copies/mL cutoff drive major patient management decisions and clinical study outcomes. METHODS: A total of 2217 samples were collected from 1922 HIV-1-infected subjects taking antiretroviral therapy for at least 48 weeks and had at least 2 consecutive samples with HIV-1 RNA <50 copies/mL by Amplicor from 7 recent clinical trials. HIV-1 RNA results were obtained from the Amplicor and TaqMan 2.0 assays in parallel by a reference laboratory. RESULTS: The overall concordance between assay results was 96% at the cutoff of 50 copies/mL. However, statistically significant discordance at the 50 copies/mL cutoff was found between the assays for 3.9% of samples (n = 87). By TaqMan 2.0, virologic failure defined as HIV-1 RNA ≥ 50 copies/mL was reported for 2.8% more samples than Amplicor. Of these 87 samples, 68 samples fell within the predicted range of assay variability. Retesting of HIV-1 RNA by TaqMan 2.0 confirmed the discordance in only 28 of the 87 samples. CONCLUSIONS: The TaqMan 2.0 assay reports fewer subjects below the clinical endpoint of HIV-1 RNA <50 copies/mL in HIV clinical trials than the Amplicor assay. This difference must be considered when assessing disease progression, designing clinical trials, and comparisons with historical trials that used the Amplicor assay.

Electrochemically Driven Surface-Confined Acid/Base Reaction for an Ultrafast H(+) Supercapacitor.

We discovered an organic weak acid, 3,4,9,10-perylene tetracarboxylic acid (PTCA), confined on the electrode surface, revealing a reversible and ultrafast protonation/deprotonation non-Faradaic process but exhibiting analogous voltammetric peaks (capacitive peaks). A further synthesized PTCA-graphene supramolecular nanocomplex discloses a wide voltage window (1.2 V) and ultrahigh specific capacitance up to 143 F g(-1) at an ultrafast charge-discharge density of 1000 A g(-1) (at least 1 order of magnitude faster than present speeds). The capacitance retention maintained at 73% after 5000 cycles. This unique capacitive voltammetric behavior suggests a new type of charge-storage modes, which may offer a way for overcoming the present difficulties of supercapacitors.

Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.

BACKGROUND: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. METHODS: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. FINDINGS: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. INTERPRETATION: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. FUNDING: Gilead Sciences.

Defect enabled formation of multilayered funnel from isolated graphene nanoring.

Molecular dynamics simulations demonstrate that the cut defect can induce and guide the self-assembly of an isolated graphene nanoring (GNR) to form multi-layered funnel morphology. The vdW force is the driving force; the tangent component drives the self-assembly of GNR and the normal component adjusts and maintains the vertical distance between graphene layers, which is two times of the vdW radius. Moreover, the offset π-π stacking aids the adjacent layers to achieve the lowest energy of AB stacking. With different diameters of the annular GNRs, the final configurations experience multilayered cone, funnel and tube-shaped structures. It also illustrates the influence of temperature in the funnel-forming process. The wide gap with two edges beyond the cutoff distance of vdW force can utilize fullerenes to help and induce the assembly of the GNR. Cutting defect fissure would be a new way to induce the self-assembly of isolated graphene to design and fabricate new carbon nanostructures without impurities.

Probing Bio-Nano Interactions between Blood Proteins and Monolayer-Stabilized Graphene Sheets.

Meeting proteins is regarded as the starting event for nanostructures to enter biological systems. Understanding their interactions is thus essential for a newly emerging field, nanomedicine. Chemically converted graphene (CCG) is a wonderful two-dimensional (2D) material for nanomedicine, but its stability in biological environments is limited. Systematic probing on the binding of proteins to CCG is currently lacking. Herein, we report a comprehensive study on the interactions between blood proteins and stabilized CCG (sCCG). CCG nanosheets are functionalized by monolayers of perylene leading to significant improvement in their resistance to electrolyte salts and long-term stability, but retain their core structural characteristics. Five types of model human blood proteins including human fibrinogen, γ-globulin, bovine serum albumin (BSA), insulin, and histone are tested. The main driving forces for blood protein binding involve the π-π interacations between the π-plane of sCCG and surface aromatic amonic acid (sAA) residues of proteins. Several key binding parameters including the binding amount, Hill coefficient, and binding constant are determined. Through a detailed analysis of key controlling factors, we conclude that the protein binding to sCCG is determined mainly by the protein size, the number, and the density of the sAA.

Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults.

BACKGROUND: Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. METHODS: The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. RESULTS: Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng ·â€Šh/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 µM) and 120 mg of tenofovir alafenamide (16.9 µM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 µM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log10copies/mL for the tenofovir disoproxil fumarate group, -1.57 log10 copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log10 copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. CONCLUSIONS: Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results.

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.

Cu1.4Mn1.6O4 as a bifunctional transducer for potentiometric Cu2+ solid-contact ion-selective electrode.

Current potentiometric Cu2+ sensors mostly rely on polymer-membrane-based solid-contact ion-selective electrodes (SC-ISEs) that constitute ion-selective membranes (ISM) and solid contact (SC) for respective ion recognition and ion-to-electron transduction. Herein, we report an ISM-free Cu2+-SC-ISE based on Cu-Mn oxide (Cu1.4Mn1.6O4) as a bifunctional SC layer. The starting point is simplifying complex multi-interfaces for Cu2+-SC-ISEs. Specifically, ion recognition and signal transduction have been achieved synchronously by an ion-coupled-electron transfer of crystal ion transport and electron transfer of Mn4+/3+ in Cu1.4Mn1.6O4. The proposed Cu1.4Mn1.6O4 electrode discloses comparable sensitivity, response time, high selectivity and stability compared with present ISM-based potentiometric Cu2+ sensors. In addition, the Cu1.4Mn1.6O4 electrode also exhibits near Nernstian responses toward Cu2+ in natural water background. This work emphasizes an ISM-free concept and presents a scheme for the development of potentiometric Cu2+ sensors.

Carbon fiber-based multichannel solid-contact potentiometric ion sensors for real-time sweat electrolyte monitoring.

Solid-contact ion-selective electrodes (SC-ISEs) feature miniaturization and integration that have gained extensive attention in non-invasive wearable sweat electrolyte sensors. The state-of-the-art wearable SC-ISEs mainly use polyethylene terephthalate, gold and carbon nanotube fibers as flexible substrates but suffer from uncomfortableness, high cost and biotoxicity. Herein, we report carbon fiber-based SC-ISEs to construct a four-channel wearable potentiometric sensor for sweat electrolytes monitoring (Na+/K+/pH/Cl-). The carbon fibers were extracted from commercial cloth, of which the starting point is addressing the cost and reproducibility issues for flexible SC-ISEs. The bare carbon fiber electrodes exhibited reversible voltammetric and stable impedance performances. Further fabricated SC-ISEs based on corresponding ion-selective membranes disclosed Nernstian sensitivity and anti-interface ability toward both ions and organic species in sweat. Significantly, these carbon fiber-based SC-ISEs revealed high reproducibility of standard potentials between normal and bending states. Finally, a textile-based sensor was integrated with a solid-contact reference electrode, which realized on-body sweat electrolytes analysis. The results displayed high accuracy compared with ex-situ tests by ion chromatography. This work highlights carbon fiber-based multichannel wearable potentiometric ion sensors with low cost, biocompatibility and reproducibility.