Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Prognostic factors and treatment responses among patients with gross residual disease in differentiated thyroid cancer.

BACKGROUND: Various postoperative staging systems were developed to assess the outcome of differentiated thyroid cancer (DTC) from initial risk after surgery to dynamic changing prognosis during follow-up. The objective of our retrospective cohort study was to identify risk factors contributing to macroscopic positive surgical margin (R2 resection) and parameters in discriminating the treatment responses and prognosis among R2 patients. METHODS: In total, 242 DTC patients with extrathyroidal extension who underwent a thyroidectomy at Kaohsiung Chang Gung Memorial Hospital between January 2013 and July 2018, were included. The patients were grouped according to the presence or absence of gross residual disease (R2). The R2 patients were further classified into two categories according to their treatment response into excellent and non-excellent groups. The parameters and treatment outcomes were compared between these groups. RESULTS: The mean follow-up time was 45.3 months. 207 (85.5%) patients had either surgery-free or microscopic margins (R0/R1), while 35 (14.5%) had R2 resection. In the R2 group (n = 35), 15 (42.9%) patients achieved an excellent response, while 20 (57.1%) achieved a non-excellent response. Statistically significant differences were observed in the extent of neck dissection, TSH-Tg level, post-RAI Tg level, nodal status, and recurrence between the two groups. The Kaplan-Meier curves for 5-year local and distant recurrence-free survival (LRFS and DRFS) of R0/R1 vs. R2 patients were 90.0% vs. 66.3%, and 98.4% vs.90.7% respectively, (p <0.001). Among the R2 patients, the excellent responders had a higher LRFS than non-excellent responders (93.3% vs. 45.1%, p=0.008). CONCLUSION: There are significant disparities in RFS among R2 patients with different treatment responses. The nodal status of PTC and thyroglobulin level after thyroidectomy and RAI were factors contributing to difference in their treatment responses.

Microforceps-Assisted Transscleral Fixation of Intraocular Lens.

PURPOSE: We present a novel technique for intraocular lens (IOL) fixation. The technique can be used on single-piece acrylic IOLs and can manage the patients who are either aphakia or with a dislocated IOL. METHODS: One end of Gore-Tex suture is tied into the optic-haptic junction of the IOL. Another end is fixated in the scleral wall. The single sclerotomy and double sclerotomies settings can be applied to different situations. RESULTS: Twelve eyes received this procedure. After a follow-up period of up to 20 months, the IOLs were well centered. CONCLUSION: The technique is a reliable method for scleral fixation of IOLs, which can be applied on the widely used single-piece acrylic IOLs. In our experience, it is reproducible and rarely cause complications.

Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling.

The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood, as neurodevelopment and structural plasticity are tightly linked. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity and synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We report that while both synapse development and activity-induced synaptic remodeling at the fly NMJ require macroautophagy (hereafter referred to as autophagy), bifurcation in the autophagy pathway differentially impacts development and synaptic plasticity. We demonstrate that neuronal activity enhances autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma.

BACKGROUND AND PURPOSE: For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODS: Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTS: Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0-36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7-35.9 Gy). CONCLUSION: IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

Omega-3 Fatty Acids for Depression in the Elderly and Patients with Dementia: A Systematic Review and Meta-Analysis.

This study aimed to evaluate the efficacy of omega-3 fatty acid supplementation interventions in improving depression in patients with dementia. To achieve this objective, randomized controlled trials (RCTs) were identified from primary electronic databases, focusing on the relationship between omega-3 fatty acids and depression in patients with dementia. The primary outcome was the impact of omega-3 fatty acids on post-intervention depression in patients with dementia, with subgroup analyses conducted based on the type of intervention (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) combination), duration of intervention (3 months, 6 months, 12 months, ≥24 months), cognitive function (ranging from mild cognitive impairment (MCI) to severe dementia), and daily dosage (high, medium, low, applicable to both DHA and EPA). The study has been duly registered with PROSPERO (registration ID: CRD42023408744). A meta-analysis of five studies (n = 517) included in nine systematic reviews showed that omega-3 supplementation had a non-significant trend toward affecting depressive symptoms in patients with dementia (standardized mean difference (SMD): 0.147; 95% confidence interval (CI): -0.324 to 0.049; p = 0.141). Subgroup analyses revealed that DHA supplementation significantly reduced depressive symptoms (SMD: -0.247; p = 0.039). There was no significant effect for high (SMD: -0.169; 95% CI: -0.454 to 0.116; p = 0.246) or medium (SMD: -0.061; 95% CI: -0.228 to 0.105; p = 0.470) doses of EPA. However, low doses of EPA were significantly effective (SMD: -0.953; 95% CI: -1.534 to -0.373; p = 0.001), with notable improvements in patients with MCI (SMD: -0.934; p < 0.001). The study concludes that omega-3 fatty acids, particularly through DHA supplementation, may alleviate depressive symptoms in patients with MCI. Given the limited sample size, further long-term RCTs are recommended to better understand the efficacy and optimal management of omega-3 supplementation in this population using different dosages.

A novel biodegradable magnesium skin staple: A safety and functional evaluation.

BACKGROUND: The potential of biodegradable magnesium (Mg) skin staple has recently garnered widespread attention due to their biodegradability and biocompatibility rather than traditional stainless steel staples, the most commonly used in current clinical practice. The aim of this study is to evaluate the safety and mechanical properties of a novel biodegradable Mg skin staple. METHODS: A prototype of Mg skin staple was designed using a novel ZK60 Mg alloy. The mechanical properties of the staple were evaluated using a universal testing machine. The cytotoxicity of the staple was examined in vitro and the efficacy of the staple in wound closure was assessed in New Zealand rabbits for one and three weeks, respectively. RESULTS: The tensile strength of this Mg alloy is 258.4 MPa with 6.9% elongation. The treatment of HaCaT and L929 cells with the staple extract resulted in over 95% cell viability, indicating no cytotoxicity. In vivo, no tissue irritation was observed. No difference was found in wound healing between the Mg skin staple and the stainless steel staple after one and three weeks in the cutting wound on the back of rabbits. Some Mg skin staples spontaneously dislodged from the skin within three weeks, while others were easily removed. CONCLUSION: Our results confirm the safety, biocompatibility, and functionality of the novel Mg skin staple in wound closure. The efficacy of the staple in wound closure was demonstrated to be as effectively as conventional staples, with the added benefit of decreased long-term retention of skin staples in the wounds.

Legal or illegal? -Transferring jurisdiction in the course of maritime law enforcement.

In order to safeguard China's existing interests and position in the South China Sea and to protect the peace and stability of the South China Sea region, the article examines the current status of the U.S. Coast Guard's activities in the South China Sea region. Using the method of the literature research and comparative research, it analyses the legal basis of the U.S. Coast Guard's activities in the South China Sea as well as the legality of law enforcement in the disputed waters through "Shiprider Agreement". This paper argues that the U.S. Coast Guard will further strengthen its presence in the South China Sea by signing a "Shiprider Agreement" with Vietnam and other South China Sea coastal states in order to gain jurisdiction over the so-called "exclusive economic zone" and carry out fisheries enforcement activities. Generally speaking, a country can transfer part of its sovereign rights to an organization or another country in a cooperative relationship in order to maximize its national interests. The United States unilaterally regarded the disputed waters in the South China Sea as "a country's exclusive economic zone" and acquired jurisdiction through the "Shiprider Agreement" in violation of international custom and the rules of international law. In light of the potential U.S. actions in the South China Sea, it is recommended that China sign bilateral treaties with all parties in the South China Sea to facilitate cooperation, and strengthen the means of support of the Coast Guard Law in order to safeguard China's existing interests and positions in the South China Sea and maintain peace and stability in the region.

Design and synthesis of polypyrrole conductive ink based on sulfated chitosan for bactericide carbendazim detection.

Conductive polymers (CPs) are typically insoluble in solvents, and devising biocompatible hydrophilic CPs is challenging and imperative to expand the applications of CPs. Herein, sulfated chitosan (SCS) is used as a green dopant instead of toxic poly(styrene sulfonate) (PSS), and SCS:polypyrrole (SCS:PPy) conductive ink is prepared by in situ polymerization. Due to the complex structure between PPy and SCS polyanion, the synthesized SCS:PPy dispersion forms a well-connected electric pathway and confers superior conductivity, dispersion stability, good film-forming ability, and high electrical stability. As proof of our concept, electrochemical sensing utilizing an SCS:PPy-modified screen-printed carbon electrode (SPCE) was performed towards carbendazim (CBZ). The SCS:PPy on the SPCE surface displayed greater sensitivity to CBZ because the conductive complex structure eased the electrocatalytic action of SCS:PPy by dramatically increasing the current intensity of CBZ oxidation and notably ameliorating stability. The sensor unveils the lowest detection value of 1.02 nM with a linear range of 0.05 to 906 µM for sensing trace CBZ by utilizing the pulse voltammetry technique. Interestingly, this senor shows excellent selectivity towards CBZ due to the formation of substantial interactions between SCS:PPy and CBZ, as demonstrated by molecular simulation studies. Furthermore, this sensor can precisely monitor CBZ in actual fruit and river water samples with satisfactory results. This study sheds light on the design and synthesis of sustainable hydrophilic CPs in the fabrication of sensors.

Harnessing HfO2 Nanoparticles for Wearable Tumor Monitoring and Sonodynamic Therapy in Advancing Cancer Care.

Addressing the critical requirement for real-time monitoring of tumor progression in cancer care, this study introduces an innovative wearable platform. This platform employs a thermoplastic polyurethane (TPU) film embedded with hafnium oxide nanoparticles (HfO2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO2 film, acting as a dielectric elastomer (DE) strain sensor, undergoes proportional deformation in response to changes in the tumor volume, thereby influencing its electrical impedance. This distinctive behavior empowers the DE strain sensor to continuously and accurately monitor alterations in tumor volume, determining the optimal timing for initiating HfO2 NP treatment, optimizing dosages, and assessing treatment effectiveness. Seamless integration with a wireless system allows instant transmission of detected electrical impedances to a smartphone for real-time data processing and visualization, enabling immediate patient monitoring and timely intervention by remote medical staff. By combining the dynamic tumor monitoring capabilities of the TPU-HfO2 film with the sonosensitizer potential of HfO2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.

Protein-Aided Synthesis of Copper-Integrated Polyaniline Nanocomposite Encapsulated with Reduced Graphene Oxide for Highly Sensitive Electrochemical Detection of Dimetridazole in Real Samples.

Dimetridazole (DMZ) is a derivative of nitroimidazole and is a veterinary drug used as an antibiotic to treat bacterial or protozoal infections in poultry. The residues of DMZ cause harmful side effects in human beings. Thus, we have constructed a superior electrocatalyst for DMZ detection. A copper (Cu)-integrated poly(aniline) (PANI) electrocatalyst (PANI-Cu@BSA) was prepared by using a one-step method of biomimetic mineralization and polymerization using bovine serum albumin (BSA) as a stabilizer. Then, the synthesized PANI-Cu@BSA was encapsulated with reduced graphene oxide (rGO) using an ultrasonication method. The PANI-Cu@BSA/rGO nanocomposite had superior water dispersibility, high electrical conductivity, and nanoscale particles. Moreover, a PANI-Cu@BSA/rGO nanocomposite-modified, screen-printed carbon electrode was used for the sensitive electrochemical detection of DMZ. In phosphate buffer solution, the PANI-Cu@BSA/rGO/SPCE displayed a current intensity greater than PANI-Cu@BSA/SPCE, rGO/SPCE, and bare SPCE. This is because PANI-Cu@BSA combined with rGO increases fast electron transfer between the electrode and analyte, and this synergy results in analyte-electrode junctions with extraordinary conductivity and active surface areas. PANI-Cu@BSA/rGO/SPCE had a low detection limit, a high sensitivity, and a linear range of 1.78 nM, 5.96 µA µM-1 cm-2, and 0.79 to 2057 µM, respectively. The selective examination of DMZ was achieved with interfering molecules, and the PANI-Cu@BSA/rGO/SPCE showed excellent selectivity, stability, repeatability, and practicability.

Synthesis of High-Value Bio-Based Polyamide 12,36 Microcellular Foams with Excellent Dimensional Stability and Shape Recovery Properties.

The search for alternatives to petroleum-based thermoplastic polyamide elastomers (TPAEs) has recently drawn great interest. In this study, a bio-massed TPAE, PA12,36, was synthesized using 1,12-dodecanediamine (DDA) and fatty dimer acid (FDA, PripolTM1009) precursors via catalyst and solvent-free melt polycondensation. The molecular structure and molecular weight of the PA12,36 were characterized by 1H NMR, FTIR, and GPC. PA12,36 displayed a low melting temperature of 85.8 °C, an initial degradation temperature of 425 °C, and a glass-transition temperature of 30.4 °C, whereas it sustained satisfactory tensile strength (10.0 MPa) and superior strain at break (1378%). Furthermore, PA12,36 was foamed by supercritical CO2, and the cell size, cell density, and porosity were determined. The entangled long-chained FDA component generated a physically crosslinked network, which promoted the melt viscosity of PA12,36 against elongations of foam cell growth and increased foamability significantly. As a result, uniform structured cellular foams with a cell diameter of 15-24 µm and high cell density (1011 cells/cm3-1012 cells/cm3) were successfully achieved. The foaming window was widened from 76 to 81 °C, and the expansion ratio was increased from 4.8 to 9.6. Additionally, PA12,36 foam with a physically crosslinked structure presented a better creep shape recovery percentage (92-97.9%) and sturdier dimensional stability. This bio-based PA12,36 foam is a promising candidate to replace petroleum-based thermoplastic elastomer foams for engineering applications, particularly shoe soles.

Paediatric radiotherapy in the United Kingdom: an evolving subspecialty and a paradigm for integrated teamworking in oncology.

Many different malignancies occur in children, but overall, cancer in childhood is rare. Survival rates have improved appreciably and are higher compared with most adult tumour types. Treatment schedules evolve as a result of clinical trials and are typically complex and multi-modality, with radiotherapy an integral component of many. Risk stratification in paediatric oncology is increasingly refined, resulting in a more personalized use of radiation. Every available modality of radiation delivery: simple and advanced photon techniques, proton beam therapy, molecular radiotherapy, and brachytherapy, have their place in the treatment of children's cancers. Radiotherapy is rarely the sole treatment. As local therapy, it is often given before or after surgery, so the involvement of the surgeon is critically important, particularly when brachytherapy is used. Systemic treatment is the standard of care for most paediatric tumour types, concomitant administration of chemotherapy is typical, and immunotherapy has an increasing role. Delivery of radiotherapy is not done by clinical or radiation oncologists alone; play specialists and anaesthetists are required, together with mould room staff, to ensure compliance and immobilization. The support of clinical radiologists is needed to ensure the correct interpretation of imaging for target volume delineation. Physicists and dosimetrists ensure the optimal dose distribution, minimizing exposure of organs at risk. Paediatric oncology doctors, nurses, and a range of allied health professionals are needed for the holistic wrap-around care of the child and family. Radiographers are essential at every step of the way. With increasing complexity comes a need for greater centralization of services.

Correlates of the Veterans Visiting Emergency Departments in Taiwan: A Comparison Before and After the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Taiwan has a substantial number of veterans, but knowledge regarding their emergency department (ED) visits during the coronavirus disease 2019 (COVID-19) pandemic remains limited. This study examined the characteristics of veterans' ED visits during Taiwan's COVID-19 epidemic. METHODS: This was a cross-sectional study conducted at the ED of a large veteran medical center located in Taipei, Taiwan, from May 2018 to October 2021. We analyzed the numbers and features of visits in summer and autumn according to the first wave of the COVID-19 epidemic in Taiwan in 2021. RESULTS: Medical institutions were positively associated with veteran status. Emergency department complaints of trauma (adjusted odds ratio [AOR] = 1.15, 95% CI: 1.06-1.25; summer P < .01) and chest pain/tightness (AOR = 1.65, 95% CI: 1.45-1.87; summer P < .01; AOR = 1.4, 95% CI: 1.26-1.55; P < .01) were associated with increased odds of being a veteran. Triage levels above 2 were positively associated with veteran status in the autumn model (AOR = 1.14, 95% CI: 1.07-1.22; P < .01). Patients hospitalized after ED visits were associated with reduced odds of veteran status (P < .01). Those who spent a long time in the ED were more likely to be veterans than those who spent a shorter time in the ED (P < .01). Veterans were less likely to visit the ED regardless of the time frame of the study period (P < .01), except during the COVID-19 outbreak in the autumn (2019-2020). CONCLUSIONS: The distinctions in ED visits highlighted the individuality of veterans' medical needs. Our findings suggest that the veteran medical system can add to the focus on improving senior-friendly care, fall prevention, quality of life of institutionalized veterans, access for homeless veterans, and care for ambulatory care-sensitive conditions.

Frontier issues in international ocean governance: Japan's discharge of nuclear contaminated water into the sea.

This paper aimed at explore international ocean governance issues through the perspective of Japan's nuclear contaminated water discharge to the sea. This paper analyzes the core issue of Japan's plan to discharge nuclear contaminated water into the ocean from the perspectives of Japan's international legal obligation, law enforcement issues, and judicial issues after integrated analyzing academic research paper and cases. Japan has obligations such as timely notification, information disclosure, environmental impact assessment, and avoidance of transboundary harm. Intergovernmental and non-governmental international organizations, such as IAEA, IMO and WHO should play a role in setting up an international group of experts to carry out monitoring and assessment, and whose positions and attitudes are important references for judging Japan's behavior. Cases heard before ICJ, ITLOS, and advisory opinion proceeding could provide reference from the judicial perspective on the issue of transboundary harm and proof of damages. Furthermore, this paper discusses the response strategies that the international community especially the opponents may adopt, including promoting the adoption of relevant treaties, take a combination of requesting advisory opinion and file arbitration, establish effective international monitoring mechanism, and engage in close communication with stakeholders.

Patient-Reported Outcomes in KEYNOTE-564: Adjuvant Pembrolizumab Versus Placebo for Renal Cell Carcinoma.

BACKGROUND: In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. PATIENTS AND METHODS: In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. RESULTS: No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (-2.5; 95% CI -5.2 to 0.1), EORTC QLQ-C30 physical functioning (-0.87; 95% CI -2.7 to 1.0), and FKSI-DRS (-0.7; 95% CI -1.2 to -0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). CONCLUSIONS: Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03142334.

Neutrophil-targeted combinatorial nanosystems for suppressing bacteremia-associated hyperinflammation and MRSA infection to improve survival rates.

There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.

Single-shot observation of nonlinear pulse splitting in a Kerr medium.

We report single-shot, time-resolved observation of self-steepening and temporal splitting of near-infrared, 50 fs, micro-joule pulses propagating nonlinearly in flint (SF11) glass. A coherent, smooth-profiled, 60-nm-bandwidth probe pulse that propagated obliquely to the main pulse through the Kerr medium recorded a time sequence of longitudinal projections of the main pulse's induced refractive index profile in the form of a phase-shift "streak," in which frequency-domain interferometry recovered with ∼10 fs temporal resolution. A three-dimensional simulation based on a unidirectional pulse propagation equation reproduced observed pulse profiles.