Endoskeleton Soft Multi-Fingered Hand with Variable Stiffness.

The use of a soft multi-fingered hand in handling fragile objects has been widely acknowledged. Nevertheless, high flexibility often results in decreased load capacity, necessitating the need for variable stiffness. This article introduces a new soft multi-fingered hand featuring variable stiffness. The finger of the hand has three chambers and an endoskeleton mechanism. Two chambers facilitate bending and swinging motions, whereas the third adjusts stiffness. An endoskeleton mechanism is embedded in the third chamber, and the friction between its moving parts increases as negative air pressure rises, causing the finger's stiffness to increase. This mechanism can alter its stiffness in any configuration, which is particularly useful in manipulating irregular-shaped fragile objects post-grasping. The effectiveness of the proposed soft multi-fingered hand is validated through five experiments: stiffness adjustment, finger stiffening under a specific orientation, bulb screwing, heavy object lifting, and bean curd grasping. The results demonstrate that the proposed soft multi-fingered hand exhibits robust grasping capabilities for various fragile objects.

Safety of teropavimab and zinlirvimab with lenacapavir once every 6 months for HIV treatment: a phase 1b, randomised, proof-of-concept study.

BACKGROUND: Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen. METHODS: This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per µL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040. FINDINGS: Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per µL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL. INTERPRETATION: Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1. FUNDING: Gilead Sciences.

Testicular volume is a noninvasive predictor of sperm retrieval failure in idiopathic nonobstructive azoospermia.

ABSTRACT: We investigated the prognostic importance of noninvasive factors in predicting sperm retrieval failure in idiopathic nonobstructive azoospermia (iNOA). We studied 193 patients with nonobstructive azoospermia who underwent microsurgical testicular sperm extraction. The Chi-square test and Mann-Whitney U tests for clinical parameters and seminiferous tubule distribution were used for between-group comparisons. A logistic regression analysis was conducted to identify predictors of retrieval failure. Area under the receiver operating characteristic curve for each variable was evaluated, and the net clinical benefit was calculated using a clinical decision curve. Patients with iNOA had a lower sperm retrieval rate than those with known causes. Moreover, testicular volume was an independent factor affecting sperm extraction outcomes (odds ratio = 0.79, P < 0.05). The testicular volume cut-off value was 6.5 ml (area under the curve: 0.694). The patients with iNOA were categorized into two groups on the basis of the distribution of seminiferous tubules observed. The sperm retrieval rate and testicular volume were significantly different between the groups with a uniform or heterogeneous tubule distribution. There was also a significant association between a uniform tubule distribution and testicular volume. In conclusion, a testicular volume of more than 6.5 ml effectively predicts microsurgical testicular sperm extraction failure due to a uniform tubule distribution in patients with iNOA.

Comparative evaluation of double- and single-armed two-suture longitudinal intussusception techniques in microsurgical vasoepididymostomy: An updated systematic review and meta-analysis.

BACKGROUND: This study aimed to compare the outcomes of double-armed two-suture longitudinal intussusception microsurgical vasoepididymostomy (LIVE) and single-armed two-suture LIVE techniques in patients with epididymal obstructive azoospermia (EOA). The main outcomes assessed were patency rates, patency time, semen quality and natural pregnancy rates. METHODS: Data from patients with EOA who underwent two-suture LIVE were obtained from databases including PubMed, EMBASE, and Web of Science. Weighted data were analyzed using a random-effects model, and weighted mean differences were reported. RESULTS: A total of 1574 patients with EOA from 24 studies were included. The overall patency rate was approximately 68% (95% confidence interval [CI]: 63-72%), with a patency time of approximately 4.63 months (95% CI: 4.15-5.12). The sperm concentration reached 26.90 million/ml and the sperm motility was 23.74%. The natural pregnancy rate was 38% (95% CI: 31-46%). The different definitions of patency do not seem to have any meaningful impact when comparing patency rates. There was no significant difference in patency rates, patency time, semen quality and natural pregnancy rates between the double-armed and single-armed LIVE techniques. CONCLUSION: The single-armed LIVE is a potential alternative surgical option when high quality double-needle sutures are not easily accessible.

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy: 96-week pooled analysis.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/mL) and changes in CD4+ cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF (N=519) maintained high levels of virologic suppression (99.5% and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4+ cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events (AEs) after switching, with diarrhea, weight gain and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 AEs or serious AEs. Two participants discontinued B/F/TAF due to treatment-related AEs. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSIONS: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

A hydrogel-based first-aid tissue adhesive with effective hemostasis and anti-bacteria for trauma emergency management.

BACKGROUND: Clinical tissue adhesives remain some critical drawbacks for managing emergency injuries, such as inadequate adhesive strength and insufficient anti-infection ability. Herein, a novel, self-healing, and antibacterial carboxymethyl chitosan/polyaldehyde dextran (CMCS/PD) hydrogel is designed as the first-aid tissue adhesive for effective trauma emergency management. METHODS: We examined the gel-forming time, porosity, self-healing, antibacterial properties, cytotoxicity, adhesive strength, and hemocompatibility. Liver hemorrhage, tail severance, and skin wound infection models of rats are constructed in vivo, respectively. RESULTS: Results demonstrate that the CMCS/PD hydrogel has the rapid gel-forming (~ 5 s), good self-healing, and effective antibacterial abilities, and could adhere to tissue firmly (adhesive strength of ~ 10 kPa and burst pressure of 327.5 mmHg) with excellent hemocompatibility and cytocompatibility. This suggests the great prospect of CMCS/PD hydrogel in acting as a first-aid tissue adhesive for trauma emergency management. The CMCS/PD hydrogel is observed to not only achieve rapid hemostasis for curing liver hemorrhage and tail severance in comparison to commercial hemostatic gel (Surgiflo ®) but also exhibit superior anti-infection for treating acute skin trauma compared with clinical disinfectant gel (Prontosan ®). CONCLUSIONS: Overall, the CMCS/PD hydrogel offers a promising candidate for first-aid tissue adhesives to manage the trauma emergency. Because of the rapid gel-forming time, it could also be applied as a liquid first-aid bandage for mini-invasive surgical treatment.

Direct Observation of Magnetic Skyrmions and Their Current-Induced Dynamics in Epitaxial Single-Crystal Oxide Films.

Magnetic skyrmions are scarcely investigated for single-crystal quality films, for which skyrmions may have a remarkable performance. Even in the limited studies in this aspect, the skyrmions are usually probed by the topological Hall effect, missing important information on dynamic properties. Here, we present a comprehensive investigation on the generation/manipulation of magnetic skyrmions in La0.67Ba0.33MnO3 single-crystal films. Using the technique of magnetic force microscopy, the current-driven skyrmion dynamics are directly observed. Unlike isolated skyrmions produced by magnetic field alone, closely packed skyrmions can be generated by electric pulses in a magnetic background, with a high density (∼60/µm2) and a small size (dozens of nanometers). The threshold current moving skyrmions is ∼2.3 × 104 A/cm2, 2-3 orders of magnitude lower than that required by metallic multilayers or van der Waals ferromagnetic heterostructures. Our work demonstrates the great potential of single-crystal oxide films in developing skyrmion-based devices.

Research advances in imaging markers for predicting hematoma expansion in intracerebral hemorrhage: a narrative review.

Introduction: Stroke is a major global health concern and is ranked as the second leading cause of death worldwide, with the third highest incidence of disability. Intracerebral hemorrhage (ICH) is a devastating form of stroke that is responsible for a significant proportion of stroke-related morbidity and mortality worldwide. Hematoma expansion (HE), which occurs in up to one-third of ICH patients, is a strong predictor of poor prognosis and can be potentially preventable if high-risk patients are identified early. In this review, we provide a comprehensive summary of previous research in this area and highlight the potential use of imaging markers for future research studies. Recent advances: Imaging markers have been developed in recent years to aid in the early detection of HE and guide clinical decision-making. These markers have been found to be effective in predicting HE in ICH patients and include specific manifestations on Computed Tomography (CT) and CT Angiography (CTA), such as the spot sign, leakage sign, spot-tail sign, island sign, satellite sign, iodine sign, blend sign, swirl sign, black hole sign, and hypodensities. The use of imaging markers holds great promise for improving the management and outcomes of ICH patients. Conclusion: The management of ICH presents a significant challenge, and identifying high-risk patients for HE is crucial to improving outcomes. The use of imaging markers for HE prediction can aid in the rapid identification of such patients and may serve as potential targets for anti-HE therapies in the acute phase of ICH. Therefore, further research is needed to establish the reliability and validity of these markers in identifying high-risk patients and guiding appropriate treatment decisions.

Inflatable Metamorphic Origami.

This study created a new type of inflatable metamorphic origami that has the advantage of being a highly simplified deployable system capable of realizing multiple sequential motion patterns with a monolithic actuation. The main body of the proposed metamorphic origami unit was designed as a soft inflatable metamorphic origami chamber with multiple sets of contiguous/collinear creases. In response to pneumatic pressure, the metamorphic motions are characterized by an initial unfolding around the first set of contiguous/collinear creases followed by another unfolding around the second set of contiguous/collinear creases. Furthermore, the effectiveness of the proposed approach was verified by constructing a radial deployable metamorphic origami for supporting the deployable planar solar array, a circumferential deployable metamorphic origami for supporting the deployable curved-surface antenna, a multi-fingered deployable metamorphic origami grasper for grasping large-sized objects, and a leaf-shaped deployable metamorphic origami grasper for capturing heavy objects. The proposed novel metamorphic origami is expected to serve as a foundation for designing lightweight, high-deploy/fold-ratio, low-energy-consumption space deployable systems.

Bictegravir/emtricitabine/tenofovir alafenamide as initial treatment for HIV-1: five-year follow-up from two randomized trials.

Background: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks. Methods: Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10). Findings: Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/µL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6). Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%. Interpretation: Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV. Funding: Gilead Sciences.

Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats.

Varicocele is regarded as the main factor that contributes to male infertility. This study aimed to explore the effect of CAMK2D on spermatogonia in the testis of experimental varicocele rats. The experimental varicocele model was established in rats and treated using different ligation methods. mRNA expression profile analysis was performed on the left testicular tissue isolated from different groups, and differentially expressed genes (DEGs) were analysed by bioinformatics methods and identified by qRT-PCR. The effect of CAMK2D, the screened DEG, on the proliferation of spermatogonia was evaluated by CCK-8 assay. The expression level of the c-kit was measured by the immunofluorescence assay and the expression levels of CAMKII, FOXO1, and ß-catenin were detected by qRT-PCR and western blotting. Five DEGs (i.e., TMCC3, FLNB, CAMK2D, OPLAH, and EGR1) were screened using the comprehensive analysis of mRNA high-throughput sequencing data. TMCC3 and FLNB were significantly downregulated, and CAMK2D, OPLAH, and EGR1 were dramatically upregulated in the testicular tissue of varicocele rats. The target DEG CAMK2D was obtained through identification by using qRT-PCR. In vitro assays revealed that the proliferation of spermatogonia was significantly facilitated by the silencing of CAMK2D, which resulted in the downregulation of CAMKII, FOXO1, and ß-catenin. In conclusion, silencing CAMK2D facilitated the proliferation of spermatogonia in the testis of experimental varicocele rats.

Modulation of T Cell Responses by Fucoidan to Inhibit Osteogenesis.

Fucoidan has sparked considerable interest in biomedical applications because of its inherent (bio)physicochemical characteristics, particularly immunomodulatory effects on macrophages, neutrophils, and natural killer cells. However, the effect of fucoidan on T cells and the following regulatory interaction on cellular function has not been reported. In this work, the effect of sterile fucoidan on the T-cell response and the subsequent modulation of osteogenesis is investigated. The physicochemical features of fucoidan treated by high-temperature autoclave sterilization are characterized by UV-visible spectroscopy, X-ray diffraction, Fourier transform infrared and nuclear magnetic resonance analysis. It is demonstrated that high-temperature autoclave treatment resulted in fucoidan depolymerization, with no change in its key bioactive groups. Further, sterile fucoidan promotes T cells proliferation and the proportion of differentiated T cells decreases with increasing concentration of fucoidan. In addition, the supernatant of T cells co-cultured with fucoidan greatly suppresses the osteogenic differentiation of MC3T3-E1 by downregulating the formation of alkaline phosphatase and calcium nodule compared with fucoidan. Therefore, our work offers new insight into the fucoidan-mediated T cell and osteoblast interplay.

Regulation of T Cell Responses by Nano-Hydroxyapatite to Mediate the Osteogenesis.

Nano-hydroxyapatite (nHA) has been widely applied as a tissue-engineering biomaterial and interacted with osteoblasts/stem cells to repair bone defects. In addition, T cells that coexist with osteoblasts/stem cells in the bone modulate the regulation of osteoimmunology by cytokine formation. However, the effects of nHA on T cells and the following regulatory interplay on osteogenic differentiation have been rarely examined. In this work, the physicochemical properties of needle-like nHA are characterized by field emission scanning electron microscopy, zeta potential, Fourier transform-infrared and X-ray diffraction. It is found that as the concentration of nHA increases, the proliferation of T cells gradually increases, and the proportion of apoptotic T cells decreases. The percentage of CD4+ T cells is higher than that of CD8+ T cells under the regulation of needle-like nHA. Furthermore, the supernatant of T cells co-cultured with nHA significantly inhibits the osteogenic differentiation of MC3T3-E1 by downregulating the formation of alkaline phosphatase and calcium nodule compared with the supernatant of nHA. Thus, our findings provide new insight into the nHA-mediated T cell and osteoblast interactions.

Preparation of triamcinolone acetonide-loaded chitosan/fucoidan hydrogel and its potential application as an oral mucosa patch.

Oral inflammatory diseases (OIDs) are among the most common lesions in the oral cavity, affecting the quality of human life and even causing oral cancer. However, most of the current oral mucosa patches still have some limitations, particularly instant, poor mechanical strength and conformability, low adhesion to tissue, and foreign body sensation. Herein, triamcinolone acetonide (TA)-loaded chitosan/fucoidan (CF) composite hydrogels were prepared via chemical crosslinking. The macro/microscopic morphologies and (bio)physicochemical properties of composite hydrogels were investigated. Incorporating fucoidan in chitosan hydrogels greatly enhanced their swelling behavior, mechanical strength, and adhesion properties. Further, the addition of TA in CF hydrogels improved their elastic feature, inhibited inflammatory response, and promoted the formation of mature and well-organized collagen fibers. The developed composite hydrogels displayed not only good antibacterial properties but also good cytocompatibility and histocompatibility. Thus, the designed hydrogels allow the development of oral mucosa patches as a potential treatment for OIDs.

First Report of Oxacillin Susceptible mecA-Positive Staphylococcus aureus in a Children's Hospital in Kunming, China.

PURPOSE: The present study investigated the prevalence characteristics of oxacillin susceptible mecA-positive Staphylococcus aureus (OS-MRSA) in a children's hospital in Kunming from January 2019 to December 2020. METHODS: A total of 499 S. aureus strains were included in the study and tested for oxacillin susceptibility using the VITEK 2 Compact automated antimicrobial susceptibility test system. All oxacillin-susceptible strains were detected mecA and mecC by polymerase chain reaction (PCR). E-test was used to compare the minimum inhibitory concentration (MIC) values of methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and OS-MRSA for oxacillin, cefoxitin, penicillin, vancomycin, erythromycin, and clindamycin. Molecular typing of OS-MRSA was performed by MLST and SCCmec typing. Toxin genes were detected by PCR. RESULTS: Forty-five OS-MRSA strains were detected, for an overall rate of 9.02% (45/499). The MICs of MSSA, OS-MRSA, and MRSA against oxacillin were concentrated at 0.38, 0.38, and 12 µg/mL, respectively; the cefoxitin MICs of MSSA and MRSA were concentrated at 2 and 32 µg/mL respectively; and MICs of OS-MRSA were concentrated at 2 and 8 µg/mL; penicillin, vancomycin and erythromycin MICs against MSSA, OS-MRSA, and MRSA showed same centralized points and were 32, 1, and 256 µg/mL, respectively; the MICs of clindamycin against MSSA were 0.5 µg/mL, while that against OS-MRSA and MRSA were concentrated at 256 µg/mL. Molecular typing of OS-MRSA was dominated by ST59-SCCmec IV. The carrier rates of hemolysin genes (hl-a, hl-d) and fibrinogen-binding clumping factor genes (clfA, clfB) were 100% in OS-MRSA, followed by 40% (18/45) for enterotoxin genes (sea, seb). CONCLUSION: OS-MRSA has a high detection rate in children, and main molecular typing is ST59-SCCmecIV in Kunming. The identification ability of automated antibacterial drug sensitivity test detection systems for OS-MRSA is very limited. A combination of phenotypic analysis and molecular detection should be used to improve OS-MRSA identification.

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.

Three-year study of pre-existing drug resistance substitutions and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in HIV-1 treatment-naive participants.

OBJECTIVES: Two Phase 3, randomized, double-blind, active-controlled studies of initial HIV-1 treatment demonstrated that bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) was non-inferior to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC; Study 1489) or to DTG+F/TAF (Study 1490) through 144 weeks. In both studies, there was no emergent resistance to study drugs. Here, the 3 year resistance analysis and impact of baseline resistance substitutions on treatment response are described. METHODS: Population sequencing of HIV-1 protease and reverse transcriptase (RT) was performed at screening. Retrospective baseline next generation sequencing of protease, RT and integrase (IN) was analysed at a ≥ 15% cutoff. Resistance analyses were performed on participants with confirmed viral rebound of HIV-1 RNA ≥200 copies/mL through Week 144 or last visit who did not resuppress to <50 copies/mL while on study drug. RESULTS: Transmitted primary drug resistance substitutions were present in the following proportions of participants: integrase strand transfer inhibitor (INSTI) resistance (-R) in 1.3% (17/1270) of participants; NRTI-R in 2.7% (35/1274); NNRTI-R in 14.1% (179/1274); and PI-R in 3.5% (44/1274). These pre-existing resistance substitutions not associated with study drug did not affect treatment outcomes. One participant in the B/F/TAF group had pre-existing bictegravir and dolutegravir resistance substitutions (Q148H+G140S in integrase) at baseline and suppressed and maintained HIV-1 RNA <50 copies/mL through Week 144. In total, 21 participants qualified for resistance testing [1.3% (8/634) B/F/TAF; 1.9% (6/315) DTG/ABC/3TC; 2.2% (7/325) DTG+F/TAF]; none had emergent resistance to study drugs. CONCLUSIONS: Treatment with B/F/TAF, DTG/ABC/3TC, or DTG+F/TAF achieved high, durable rates of virological suppression in HIV-1 treatment-naive participants. The presence of pre-existing resistance substitutions did not affect treatment outcomes, and there was no treatment-emergent resistance.

Serotype Distribution and Characteristics of the Minimum Inhibitory Concentrations of Streptococcus pneumoniae Isolated from Pediatric Patients in Kunming, China.

Streptococcus pneumoniae (S. pneumoniae) is the main conditional pathogen of acute respiratory infection in infants, children, and older adults worldwide. It was great significant to identify the epidemic characteristics of serotypes and antibiotic susceptibility for the prevention and treatment of S. pneumoniae diseases. This research assessed the serotype distribution and the minimum inhibitory concentrations (MICs) of S. pneumoniae isolated from pediatric patients to provide information on the epidemiology and antibiotic resistance of S. pneumoniae in Kunming, China. A total of 140 S. pneumoniae isolates were collected from pediatric patients at Kunming Children's Hospital from January 2016 to October 2017. Serotype identification was done by Quellung reaction and multiplex polymerase chain reaction. MICs were determined by E-test. 140 isolates distributed in 13 types of serotypes. The top-three prevalent serotypes were 19F, 19A, and 6B. The immunization coverage rate of 13-valent pneumococcal conjugate vaccine (PCV) was relatively higher and should be introduced into the vaccination program in the region. MIC50 of penicillin, ceftriaxone, and levofloxacin was 1 µg/mL. MIC50 for meropenem and vancomycin was 0.38 µg/mL. MIC90 of penicillin, ceftriaxone, and levofloxacin was 1.5 µg/mL and that of meropenem and vancomycin was 0.5 µg/mL. The MIC90 of erythromycin was > 256 µg/mL. In summary, S. pneumoniae had low resistance rates to penicillin, ceftriaxone, levofloxacin, vancomycin, and meropenem, and these antibiotics could be the first-line agents for children with pneumococcal infections in Kunming.

Wind Tunnel Measurement Systems for Unsteady Aerodynamic Forces on Bluff Bodies: Review and New Perspective.

Wind tunnel tests have become one of the most effective ways to evaluate aerodynamics and aeroelasticity in bluff bodies. This paper has firstly overviewed the development of conventional wind tunnel test techniques, including high frequency base balance technique, static synchronous multi-pressure sensing system test technique and aeroelastic test, and summarized their advantages and shortcomings. Subsequently, two advanced test approaches, a forced vibration test technique and hybrid aeroelastic- force balance wind tunnel test technique have been comprehensively reviewed. Then the characteristics and calculation procedure of the conventional and advanced wind tunnel test techniques were discussed and summarized. The results indicated that the conventional wind tunnel test techniques ignored the effect of structural oscillation on the measured aerodynamics as the test model is rigid. A forced vibration test can include that effect. Unfortunately, a test model in a forced vibration test cannot respond like a structure in the real world; it only includes the effect of structural oscillation on the surrounding flow and cannot consider the feedback from the surrounding flow to the oscillation test model. A hybrid aeroelastic-pressure/force balance test technique that can observe unsteady aerodynamics of a test model during its aeroelastic oscillation completely takes the effect of structural oscillation into consideration and is, therefore, effective in evaluation of aerodynamics and aeroelasticity in bluff bodies. This paper has not only advanced our understanding for aerodynamics and aeroelasticity in bluff bodies, but also provided a new perspective for advanced wind tunnel test techniques that can be used for fundamental studies and engineering applications.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials.

BACKGROUND: In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. METHODS: We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection 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 once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. FINDINGS: 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. INTERPRETATION: These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. FUNDING: Gilead Sciences.