Nanjing General Hospital of Nanjing Military Command

BACKGROUND: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. METHODS: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. CONCLUSIONS: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).

Over 50% of the human body is comprised of fluids that are distributed in defined compartments. Although compartmentalized, these fluids are dynamically connected. Fluids, electrolytes, and acid-base balance in each compartment are tightly regulated, mostly in an energy-dependent manner to achieve their designed functions. For over a century, our understanding of the microvascular fluid homeostasis has evolved from hypothesized Ernest Starling principle to evidence-based and the revised Starling principle, incorporating the functional endothelial surface layer. The kidney is a highly vascular and encapsulated organ that is exquisitely sensitive to inadequate (insufficient or excess) blood flow. The kidney is particularly sensitive to venous congestion, and studies show that reduced venous return triggers a greater degree of kidney damage than that from lacking arterial flow. Thus, fluid overload can induce severe and sustained kidney injury. In the setting of established acute kidney injury, fluid management can be challenging. Impaired capacity of urine output and urine concentration and dilution should be taken into consideration when designing fluid therapy. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=452702.

MicroRNAs (miRNAs) are a group of noncoding RNA molecules of 20-23 nucleotides length that negatively regulate gene expressions in numerous cellular processes. Through complementary paring with target mRNAs, miRNAs have frequently emerged as dual regulators of cancer development by acting on multiple signaling pathways, thereby act as novel biomarkers for cancer diagnosis, prognosis, and prediction of response to treatment. As one of them, miR-30a has been found to act as an onco-suppressor of tumorigenesis pathways through inhibition of cellular proliferation, migration and invasion. Simultaneously, miR-30a plays a progressing role in several types of cancer, determined by relevant target genes as well. In the present review, we summarize recent research regarding miR-30a, including its biological function, expression and regulation, especially focusing on its role in cancer development and progression. Clinically, miR-30a may serve as a potential target in the diagnosis and therapy of human cancer.

Acute ischemic stroke caused by internal carotid artery (ICA) occlusion usually has a poor prognosis, especially the T occlusion cases without functional collaterals. The efficacy of intravenous (IV) or intra-arterial (IA) thrombolysis with recombinant tissue plasminogen activator (rt-PA) remains ambiguous in these patients. Eendovascular recanalization of the occluded carotid has been attempted in recent years as a potential strategy. However, the different etiologies of ICA occlusion pose a significant challenge to neurointerventionists. Recently, several endovascular evolvements have been reported in treating carotid occlusion-related stroke. This review summarizes the current status of treatment for acute ICA occlusion.

BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)

A multifunctional theranostic platform based on photosensitizer-loaded plasmonic vesicular assemblies of gold nanoparticles (GNPs) is developed for effective cancer imaging and treatment. The gold vesicles (GVs) composed of a monolayer of assembled GNPs show strong absorbance in the near-infrared (NIR) range of 650-800 nm, as a result of the plasmonic coupling effect between neighboring GNPs in the vesicular membranes. The strong NIR absorption and the capability of encapsulating photosensitizer Ce6 in GVs enable trimodality NIR fluorescence/thermal/photoacoustic imaging-guided synergistic photothermal/photodynamic therapy (PTT/PDT) with improved efficacy. The Ce6-loaded GVs (GV-Ce6) have the following characteristics: (i) high Ce6 loading efficiency (up to ~18.4 wt %; (ii) enhanced cellular uptake efficiency of Ce6; (iii) simultaneous trimodality NIR fluorescence/thermal/photoacoustic imaging; (iv) synergistic PTT/PDT treatment with improved efficacy using single wavelength continuous wave laser irradiation.

BACKGROUND: Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited. METHODS: We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications. RESULTS: Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P<0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation. CONCLUSIONS: In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

The human brain is a large-scale integrated network in the functional and structural domain. Graph theoretical analysis provides a novel framework for analysing such complex networks. While previous neuroimaging studies have uncovered abnormalities in several specific brain networks in patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures, little is known about changes in whole-brain functional and structural connectivity networks. Regarding functional and structural connectivity, networks are intimately related and share common small-world topological features. We predict that patients with idiopathic generalized epilepsy would exhibit a decoupling between functional and structural networks. In this study, 26 patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures and 26 age- and sex-matched healthy controls were recruited. Resting-state functional magnetic resonance imaging signal correlations and diffusion tensor image tractography were used to generate functional and structural connectivity networks. Graph theoretical analysis revealed that the patients lost optimal topological organization in both functional and structural connectivity networks. Moreover, the patients showed significant increases in nodal topological characteristics in several cortical and subcortical regions, including mesial frontal cortex, putamen, thalamus and amygdala relative to controls, supporting the hypothesis that regions playing important roles in the pathogenesis of epilepsy may display abnormal hub properties in network analysis. Relative to controls, patients showed further decreases in nodal topological characteristics in areas of the default mode network, such as the posterior cingulate gyrus and inferior temporal gyrus. Most importantly, the degree of coupling between functional and structural connectivity networks was decreased, and exhibited a negative correlation with epilepsy duration in patients. Our findings suggest that the decoupling of functional and structural connectivity may reflect the progress of long-term impairment in idiopathic generalized epilepsy, and may be used as a potential biomarker to detect subtle brain abnormalities in epilepsy. Overall, our results demonstrate for the first time that idiopathic generalized epilepsy is reflected in a disrupted topological organization in large-scale brain functional and structural networks, thus providing valuable information for better understanding the pathophysiological mechanisms of generalized tonic-clonic seizures.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear. METHODS: Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved. RESULTS: Exosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions. CONCLUSIONS: The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.

Importance: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). Conclusions and Relevance: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration: clinicaltrials.gov Identifier: NCT01560052.

BACKGROUND: The functional architecture of the human brain has been extensively described in terms of functional connectivity networks, detected from the low-frequency coherent neuronal fluctuations that can be observed in a resting state condition. Little is known, so far, about the changes in functional connectivity and in the topological properties of functional networks, associated with different brain diseases. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated alterations related to mesial temporal lobe epilepsy (mTLE), using resting state functional magnetic resonance imaging on 18 mTLE patients and 27 healthy controls. Functional connectivity among 90 cortical and subcortical regions was measured by temporal correlation. The related values were analyzed to construct a set of undirected graphs. Compared to controls, mTLE patients showed significantly increased connectivity within the medial temporal lobes, but also significantly decreased connectivity within the frontal and parietal lobes, and between frontal and parietal lobes. Our findings demonstrated that a large number of areas in the default-mode network of mTLE patients showed a significantly decreased number of connections to other regions. Furthermore, we observed altered small-world properties in patients, along with smaller degree of connectivity, increased n-to-1 connectivity, smaller absolute clustering coefficients and shorter absolute path length. CONCLUSIONS/SIGNIFICANCE: We suggest that the mTLE alterations observed in functional connectivity and topological properties may be used to define tentative disease markers.

BACKGROUND: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. METHODS: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791. FINDINGS: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage). INTERPRETATION: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed. FUNDING: Exelixis and Ipsen.

Chlorin e6 conjugated gold nanostars (GNS-PEG-Ce6) are used to perform simultaneous photodynamic/plasmonic photothermal therapy (PDT/PPTT) upon single laser irradiation. The early-phase PDT effect is coordinated with the late-phase PPTT effect to obtain synergistic anticancer efficiency. The prepared GNS-PEG-Ce6 shows excellent water dispersibility, good biocompatibility, enhanced cellular uptake and remarkable anticancer efficiency upon irradiation in vivo.

Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals' resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.

In situ hydrogels have attracted considerable attention in tissue engineering because of their minimal invasiveness and ability to match the irregular tissue defects. However, hydrous physiological environments and the high level of moisture in hydrogels severely hamper binding to the target tissue and easily cause wound infection, thereby limiting the effectiveness in wound care management. Thus, forming an intimate assembly of the hydrogel to the tissue and preventing wound infecting still remains a significant challenge. In this study, inspired by mussel adhesive protein, a biomimetic dopamine‐modified ε‐poly‐ l ‐lysine‐polyethylene glycol‐based hydrogel (PPD hydrogel) wound dressing is developed in situ using horseradish peroxidase cross‐linking. The biomimetic catechol–Lys residue distribution in PPD polymer provides a catechol–Lys cooperation effect, which endows the PPD hydrogels with superior wet tissue adhesion properties. It is demonstrated that the PPD hydrogel can facilely and intimately integrate with biological tissue and exhibits superior capacity of in vivo hemostatic and accelerated wound repair. In addition, the hydrogels exhibit outstanding anti‐infection property because of the inherent antibacterial ability of ε‐poly‐ l ‐lysine. These findings shed new light on the development of mussel‐inspired tissue‐anchored and antibacterial hydrogel materials serving as wound dressings.

BACKGROUND: Streptococcus suis serotype 2 (S. suis 2, SS2) is a major zoonotic pathogen that causes only sporadic cases of meningitis and sepsis in humans. Most if not all cases of Streptococcal toxic shock syndrome (STSS) that have been well-documented to date were associated with the non-SS2 group A streptococcus (GAS). However, a recent large-scale outbreak of SS2 in Sichuan Province, China, appeared to be caused by more invasive deep-tissue infection with STSS, characterized by acute high fever, vascular collapse, hypotension, shock, and multiple organ failure. METHODS AND FINDINGS: We investigated this outbreak of SS2 infections in both human and pigs, which took place from July to August, 2005, through clinical observation and laboratory experiments. Clinical and pathological characterization of the human patients revealed the hallmarks of typical STSS, which to date had only been associated with GAS infection. Retrospectively, we found that this outbreak was very similar to an earlier outbreak in Jiangsu Province, China, in 1998. We isolated and analyzed 37 bacterial strains from human specimens and eight from pig specimens of the recent outbreak, as well as three human isolates and two pig isolates from the 1998 outbreak we had kept in our laboratory. The bacterial isolates were examined using light microscopy observation, pig infection experiments, multiplex-PCR assay, as well as restriction fragment length polymorphisms (RFLP) and multiple sequence alignment analyses. Multiple lines of evidence confirmed that highly virulent strains of SS2 were the causative agents of both outbreaks. CONCLUSIONS: We report, to our knowledge for the first time, two outbreaks of STSS caused by SS2, a non-GAS streptococcus. The 2005 outbreak was associated with 38 deaths out of 204 documented human cases; the 1998 outbreak with 14 deaths out of 25 reported human cases. Most of the fatal cases were characterized by STSS; some of them by meningitis or severe septicemia. The molecular mechanisms underlying these human STSS outbreaks in human beings remain unclear and an objective for further study.

PURPOSE: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348). PATIENTS AND METHODS: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

Abstract Inspired by the coordinated multiple healing mechanism of the organism, a four‐armed benzaldehyde‐terminated polyethylene glycol and dodecyl‐modified chitosan hybrid hydrogel with vascular endothelial growth factor (VEGF) encapsulation are presented for efficient and versatile wound healing. The hybrid hydrogel is formed through the reversible Schiff base and possesses self‐healing capability. As the dodecyl tails can insert themselves into and be anchored onto the lipid bilayer of the cell membrane, the hybrid hydrogel has outstanding tissue adhesion, blood cell coagulation and hemostasis, anti‐infection, and cell recruitment functions. Moreover, by loading in and controllably releasing VEGF from the hybrid hydrogel, the processes of cell proliferation and tissue remodeling in the wound bed can be significantly improved. Based on an in vivo study of the multifunctional hybrid hydrogel, it is demonstrated that acute tissue injuries such as vessel bleeding and liver bleeding can be repaired immediately because of the outstanding adhesion and hemostasis features of the hydrogel. Moreover, the chronic wound‐healing process of an infectious full‐thickness skin defect model can also be significantly enhanced by promoting angiogenesis, collagen deposition, macrophage polarization, and granulation tissue formation. Thus, this multifunctional hybrid hydrogel is potentially valuable for clinical applications.

The discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the outbreak of coronavirus disease 2019 (COVID-19) are causing public health emergencies. A handful pieces of literature have summarized its clinical and radiologic features, whereas therapies for COVID-19 are rather limited. To evaluate the efficacy of convalescent plasma therapy in COVID-19 patients, we did this timely descriptive study. Six laboratory-confirmed COVID-19 patients were enrolled and received the transfusion of ABO-compatible convalescent plasma. The efficacy of this intervention was determined by the alleviation of symptoms, changes in radiologic abnormalities and laboratory tests. No obvious adverse effect observed during the treatment. Transfusion of convalescent plasma led to a resolution of ground-glass opacities and consolidation in patients #1, #2, #3, #4, and #6. In patients #1 and #5 who presented with SARS-CoV-2 in throat swab, convalescent plasma therapy elicited an elimination of the virus. Serologic analysis indicated an immediate increase in anti-SARS-CoV-2 antibody titers in patients #2 and #3, but not in patient #1. This study indicates that convalescent plasma therapy is effective and specific for COVID-19. This intervention has a special significance for eliminating SARS-CoV-2 and is believed to be a promising state-of-the-art therapy during COVID-19 pandemic crisis.

The M-type phospholipase A2 receptor (PLA2R) is a target autoantigen in adult idiopathic membranous nephropathy (MN), but the prevalence of autoantibodies against PLA2R is unknown among Chinese patients with MN. Here, we measured anti-PLA2R antibody in the serum of 60 patients with idiopathic MN, 20 with lupus-associated MN, 16 with hepatitis B (HBV)-associated MN, and 10 with tumor-associated MN. Among patients with idiopathic MN, 49 (82%) had detectable anti-PLA2R autoantibodies using a Western blot assay; an assay with greater sensitivity detected very low titers of anti-PLA2R in 10 of the remaining 11 patients. Using the standard assay, we detected anti-PLA2R antibody in only 1 patient with lupus, 1 with HBV, and 3 with cancer, producing an overall specificity of 89% in this cohort limited to patients with secondary MN. The enhanced assay detected low titers of anti-PLA2R in only 2 additional samples of HBV-associated MN. In summary, these results suggest that PLA2R is a major target antigen in Chinese idiopathic MN and that detection of anti-PLA2R is a sensitive test for idiopathic MN.