Quality improvement of prerigor salted ground chicken breast with basic amino acids at low NaCl level.

The prerigor salting effect is known to provide superior meat processing quality. Based on the urgent need for low salt meat products, the present study was undertaken to evaluate the prerigor salting effect when basic amino acids were introduced at 1% NaCl level. Ground chicken breast meat was salted with NaCl and basic amino acids at 30 min, 60 min, and 90 min postmortem for prerigor treatments. Compared to the 1% NaCl (w/w) treatment, the introduction of 0.06% basic amino acids (w/w) in the prerigor significantly led to an increase in myofibril fragmentation, myofibrillar protein solubility, emulsion activity, storage modulus change rate, gel water-holding capacity and hardness (P < 0.05). Furthermore, smaller and more uniformly sized droplets were produced in emulsion by basic amino acids. Individual basic amino acids had different prerigor salting effects, and it was indicated that basic amino acids could play a positive role in the prerigor salting effect when NaCl was reduced.

Assessment of aerosol persistence in ICUs via low-cost sensor network and zonal models.

The COVID-19 pandemic raised public awareness about airborne particulate matter (PM) due to the spread of infectious diseases via the respiratory route. The persistence of potentially infectious aerosols in public spaces and the spread of nosocomial infections in medical settings deserve careful investigation; however, a systematic approach characterizing the fate of aerosols in clinical environments has not been reported. This paper presents a methodology for mapping aerosol propagation using a low-cost PM sensor network in ICU and adjacent environments and the subsequent development of the data-driven zonal model. Mimicking aerosol generation by a patient, we generated trace NaCl aerosols and monitored their propagation in the environment. In positive (closed door) and neutral-pressure (open door) ICUs, up to 6% or 19%, respectively, of all PM escaped through the door gaps; however, the outside sensors did not register an aerosol spike in negative-pressure ICUs. The K-means clustering analysis of temporospatial aerosol concentration data suggests that ICU can be represented by three distinct zones: (1) near the aerosol source, (2) room periphery, and (3) outside the room. The data suggests two-phase plume behavior: dispersion of the original aerosol spike throughout the room, followed by an evacuation phase where "well-mixed" aerosol concentration decayed uniformly. Decay rates were calculated for positive, neutral, and negative pressure operations, with negative-pressure rooms clearing out nearly twice as fast. These decay trends closely followed the air exchange rates. This research demonstrates the methodology for aerosol monitoring in medical settings. This study is limited by a relatively small data set and is specific to single-occupancy ICU rooms. Future work needs to evaluate medical settings with high risks of infectious disease transmission.

Measuring aerosols in the operating theatre and beyond using a real-time sensor network.

The ability to measure and track aerosols in the vicinity of patients with suspected or confirmed COVID-19 is highly desirable. At present, there is no way to measure and track, in real time, the sizes, dispersion and dilution/disappearance of aerosols that are generated by airway manipulations such as mask ventilation; tracheal intubation; bronchoscopy; dental and gastro-intestinal endoscopy procedures; or by vigorous breathing, coughing or exercise. We deployed low-cost photoelectric sensors in five operating theatres between surgical cases. We measured and analysed dilution and exfiltration of aerosols we generated to evaluate air handling and dispersion under real-world conditions. These data were used to develop a model of aerosol persistence. We found significant variation between different operating theatres. Equipment placement near air vents affects air flows, impacting aerosol movement and elimination patterns. Despite these impediments, air exchange in operating theatres is robust and prolonged fallow time before theatre turnover may not be necessary. Significant concentrations of aerosols are not seen in adjoining areas outside of the operating theatre. These models and dispersion rates can predict aerosol persistence in operating theatres and other clinical areas and potentially facilitate quantification of risk, with obvious and far-reaching implications for designing, evaluating and confirming air handling in non-medical environments.

[Single center experience of transcatheter aortic valve replacement with a simplified operative protocol].

Objective: To summarize the single center experience of transcatheter aortic valve replacement (TAVR) with a simplified operative protocol. Methods: Consecutive patients who underwent transfemoral TAVR (TF-TAVR) from July 2020 to December 2020 in Fuwai Hospital were retrospectively analyzed. We compared the baseline characteristic, procedure information, 30-day follow-up outcomes of the patients who underwent TF-TAVR without the simplified operative protocol (routine group) or with the simplified operative protocol (simplified protocol group). Results: 93 patients were collected, 42 patients belonging to routine group, 51 patients belonging to simplified protocol group. In simplified protocol group, there were 51 patients planned to use ultrasound-guided femoral access puncture, procedure was successful in all 51 patients (100%). There were 49 patients planned to use the radial artery as the secondary access, procedure was successful in 45 patients (92%). There were 48 patients planned to use the strategy of avoidance of urinary catheter, this strategy was achieved in 35 patients (73%). There were 12 patients planned to use the left ventricular guidewire to pace, procedure was successful in 11 patients (92%). There were no differences in baseline characteristics, major clinical endpoints and 30-day follow-up outcomes between the two groups. Meanwhile, the procedure time ((62.5±17.9)min vs. (78.3±16.7)min, P<0.001), operation room time ((133.7±25.1)min vs. (159.2±42.6)min, P<0.001), X-ray exposure time ((17.2±6.5)min vs. (20.2±7.7)min, P=0.027) were significantly shorten in simplified protocol group compared with the routine group. Conclusion: Our study results indicate that the simplified operative protocol of TF-TAVR is as effective and safe as the routine operative protocol, meanwhile using the simplified operative protocol can significantly increase the operative efficiency of TF-TAVR.

[Left ventricular guidewire pacing during transcatheter aortic valve replacement].

Objective: To investigate the safety and efficacy of left ventricular guidewire pacing during transcatheter aortic valve replacement (TAVR). Methods: This is a retrospective study. Thirteen patients, who underwent TAVR with left ventricular guidewire pacing from October 2019 to December 2019 in Fuwai Hospital, were included. Clinical data and operational procedure data of the patients were collected. Changes in blood pressure and electrocardiogram were observed during operations. Ascending aorta angiography was performed to evaluate the regurgitation of aortic valve after valve implantion. The incidence of major adverse cardiac events during hospitalization and at 3-months after discharge was recorded. Results: There were 7 male and 6 female patients in this cohort,and age was (73.8±8.3) years old. Among the 13 patients, 9 were tricuspid aortic valves, 3 were bicuspid aortic valves, and 1 was degenerated bioprosthetic surgical aortic valve. TAVR were successfully performed in all of the 13 cases using pacing through the left ventricular guidewire. During balloon dilation, the blood pressure decreased to below 60 mmHg (1 mmHg=0.133 kPa) after 180 beats/min pacing, and the valve release process was smooth and the position was stable. The results of aortography showed that there was no regurgitation in 7 cases, mild regurgitation in 5 cases and moderate regurgitation in 1 case. Three patients required temporary pacing during the procedure due to complete heart block, among whom 1 patient was implanted with permanent pacemaker during hospitalization, and the other 2 patients recovered within 24 hours after operation. In another case, there was no significant change of electrocardiogram during the operation, and complete heart block occurred 10 days after the operation, and treated with permanent pacemaker. The other 10 patients began to carry out bedside activities and rehabilitation training 24 hours after operation. There was no death, myocardial infarction, stroke and other major adverse cardiac events during hospitalization and at 3-month follow-up after discharge. Conclusion: Left ventricular guidewire pacing is a safe and effective strategy for TAVR.

[Feasibility of single-stage stent implantation following rotational atherectomy combined with TAVR].

Objective: To explore the feasibility of the single-stage stent implantation following rotational atherectomy combined with transcatheter aortic valve replacement (TAVR) in treating patients with severe aortic stenosis(AS) and severe calcified coronary artery stenosis. Methods: Three patients who received single-stage stent implantation following rotational atherectomy combined with TAVR in Fuwai hospital from April to October 2019 were included in this retrospective analysis. Clinical and anatomical features (including echocardiography and aortic CT) of the patients were collected, efficacy and safety of this operation strategy were observed and 6 months follow up results were summarized. Results: Three patients (2 females, 66-80 years old) were included. The mean Society of Thoracic Surgeons (STS) risk score was 7.8%. The mean maximum velocity of aortic valve was 4.4 m/s, the mean transvalvular pressure gradient was 53.2 mmHg (1 mmHg=0.133 kPa), mean left ventricular ejection fraction (LVEF) was 48.6%. All three patients had severe calcified coronary artery stenosis: left anterior descending artery (LAD, n=2) and left main coronary artery (LM, n=1), requiring rotary grinding. The mean SYNTAX score was 20. All the procedures were performed through transfemoral access. After aortic valve crossing, all coronary lesions were successfully treated with stent implantation following rotational atherectomy, transfemoral TAVR was then immediately performed with a self-expandable Venus-A valve. One patient underwent"valve-in-valve"implantation due to the high-implantation position of the first valve. The procedures were completed without complications in all the three patients. The immediate effect was satisfactory. Echocardiography results showed that the mean maximum velocity of aortic valve was 2.1 m/s, mean gradient was 9.3 mmHg, and mean LVEF was 59% after the procedure. There was no death and revascularization during the 6 months follow-up. Conclusion: In patients with severe calcified coronary artery and severe AS with high risk of cardiac surgery, the single-stage stent implantation following rotational atherectomy combined with TAVR is feasible and results are satisfactory in this patient cohort.

High Ascending Retrocecal Appendicitis in a Pediatric Patient Detected by Point-of-care Ultrasound.

A 10-year-old male presented to our pediatric emergency department with progressive, colicky abdominal pain for one day, associated with fever and non-bilious vomiting. He had a guarded abdomen with sluggish bowel sounds. He was noted to have poor perfusion with tachycardia, which resolved with fluid resuscitation. Abdominal radiograph demonstrated the presence of a circular radiopaque structure at the right hypochondrial region. Point-of-care ultrasound revealed an ascending appendicitis with signs of perforation, which was unusually located just at the inferior edge of the liver, over the right hypochondrium. The patient was immediately admitted to the surgical intermediate care unit. Urgent laparoscopic appendectomy was successfully performed, and the child was discharged well.

[Impact of aortic root morphology on the implantation depth of aortic valve prosthesis during trans-catheter aortic valve replacement in patients with native bicuspid aortic valve stenosis].

Objective: To investigate the impact of aortic root morphology on the implantation depth of aortic valve prosthesis during trans-catheter aortic valve replacement (TAVR) in bicuspid aortic valve patients. Methods: Clinical data of 40 patients with native bicuspid aortic valve stenosis who underwent TAVR using the self-expandable prosthesis (the Venus A-valve) from 2014 to 2017 in Fuwai Hospital was retrospectively analyzed. The patients were divided into non-deep implantation group (implant depth ≤10 mm by instant angiogram after implantation,29 cases) and deep implantation group (implant depth> 10 mm by instant angiogram after implantation,11 cases).Pre-procedural aortic root characteristics (e.g. calcification, angle and dimensions) were assessed by CT. The impact of aortic root morphology on the implantation depth and clinical outcomes were also evaluated. Results: The age was (75.1±5.9) years with equal representation from the raphe-type and non-raphe type (52.5%(21/40) and 47.5%(19/40)).The bigger aorta angle ((56.5±4.5)° vs. (47.4±9.4)°, P=0.004),more frequent mild-calcification (HU850, <200 mm(3)) or severe-calcification(HU850, >1 000 mm(3)) of aortic leaflets (7/11 vs. 4/29, P=0.006), as well as higher ratio of left ventricular outflow tract perimeter to annulus perimeter ((109.2±7.5)% vs. (101.5±6.5)%, P=0.004) were found in the deep implantation group compared to the non-deep implantation group. The new in-hospital onset of bundle-branchheart-block or atrioventricular block conduction disturbance rate was higher in the deep implantation group than in the non-deep implantation group (6/11 vs. 2/29, P=0.030).Left ventricular ejection fraction was similar between deep implantation group and non-deep implantation group at baseline((49.9±8.9)% vs. (55.8±10.4)%, P=0.117), and was significantly lower in the deep implantation group than in the non-deep implantation group at 30 days after implantation ((51.6±12.8)% vs. (60.9±8.1)%, P=0.020). Conclusion: Aortic root morphology of bicuspid aortic valve patients is associated with implantation depth of the prosthesis during TAVR, which affects the conduction system and left ventricular function during and post TAVR.

The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue: An in vitro and in vivo study.

OBJECTIVES: The aims of this study were to determine whether the administration of anti-inflammatory and antifibrotic agents affect the proliferation, viability, and expression of markers involved in the fibrotic development of the fibroblasts obtained from arthrofibrotic tissue in vitro, and to evaluate the effect of the agents on arthrofibrosis prevention in vivo. METHODS: Dexamethasone, diclofenac, and decorin, in different concentrations, were employed to treat fibroblasts from arthrofibrotic tissue (AFib). Cell proliferation was measured by DNA quantitation, and viability was analyzed by Live/Dead staining. The levels of procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP) were evaluated with enzyme-linked immunosorbent assay (ELISA) kits. In addition, the expressions of fibrotic markers were detected by real-time polymerase chain reaction (PCR). Fibroblasts isolated from healthy tissue (Fib) served as control. Further, a rabbit model of joint contracture was used to evaluate the antifibrotic effect of the three different agents. RESULTS: Dexamethasone maintained the viability and promoted the proliferation of AFib. Diclofenac decreased the viability and inhibited the cell proliferation during the first week of cultivation. However, decorin inhibited AFib proliferation and downregulated the expressions of fibrotic markers. Additionally, decorin could improve the flexion contracture angle and inhibit the deposition of interstitial matrix components in the rabbit joint model. CONCLUSION: Decorin decreased the expression of myofibroblast markers in AFib, inhibited the proliferation of AFib, and prevented the initial procedure of arthrofibrosis in vivo, suggesting that decorin could be a promising treatment to inhibit the development of arthrofibrosis.Cite this article: X. Tang, S. Teng, M. Petri, C. Krettek, C. Liu, M. Jagodzinski. The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue: An in vitro and in vivo study. Bone Joint Res 2018;7:213-222. DOI: 10.1302/2046-3758.73.BJR-2017-0219.R2.

Vagal Stimulation Facilitates Improving Effects of Ranolazine on Cardiac Function in Rats with Chronic Ischemic Heart Failure.

BACKGROUND: Ranolazine is generally used to treat anginal symptoms for patients with symptomatic chronic stable angina pectoris. By improving ischemiareperfusion, ranolazine is also observed to have protective effects on myocardial ischemic injury in animal models. It is noteworthy to find interventions that can decrease adverse effects of this drug and thereby increase its clinical application. METHODS: In this report, we used a rat model of chronic ischemic heart failure (CHF) to examine if vagal stimulation can strengthen the effects of ranolazine on worsened cardiac function in CHF. Plasma norepinephrine (NE) and brain natriuretic peptide [BNP, termed B-type natriuretic peptide-45 (BNP-45) in rats] are regulated by sympathetic nerve activity. Because NE and BNP are considered as neurohormones indicating heart failure progression, we also determined the levels of plasma NE and BNP-45 besides cardiac function. Moreover, we examined the role of sympathetic pro-inflammatory cytokines in engagement of vagal activation. RESULTS: Our data show that ranolazine intraperitoneally improved the impaired left ventricular function, and attenuated the exaggerated NE/BNP-45 and cytokines (such as IL-1ß, IL-6 and TNF-α) after development of CHF. Particularly, our results show that vagal activation largely amplified the effects of ranolazine on cardiac function in CHF. CONCLUSION: Our data indicate that: 1) ranolazine alleviates sympathetic nerve activity thereby leading to improvement of the worsened cardiac function in CHF; and 2) vagal stimulation augments the effect of ranolazine. Accordingly, results of this study have implications for the role played by a combination of vagal stimulation and ranolazine in improving cardiac function in CHF.

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.

[Safety and feasibility of sheathless transfemoral aortic valve implantation].

Objective: To investigate the safety and feasibility of sheathless transfemoral aortic valve replacement (TAVR). Methods: In this prospective study, we enrolled 23 patients with severe aortic stenosis (AS) who were inoperable or at high-risk for surgical aortic valve replacement operation in Fuwai hospital From September 2012 to June 2015. Multislice spiral CT and angiography of femoral artery showed that all patients had minimal femoral artery diameters (<6.5 mm) and severe calcification which was not suitable for transfemoral TAVR through sheath. We attempted to apply the sheathless transfemoral TAVR using Venus-A prosthesis without sheath insertion, and procedure related complication during the procedure and hospital stay were observed. Results: The 6 mm×30 mm balloon was used for femoral artery predilation in 1 patient with iliofemoral artery stenosis before delivery system was transported. In the other 22 patients, the delivery system was transported directly. A total of 21 patients finished TAVR with transfemoral sheathless technique. In 2 patients, prosthesis was unable to fully expand after release due to severe valve calcification, and patients received urgent surgical aortic valve replacement. One patient had valve dislocation into the ascending aorta that was not related to the sheathless replacement technique, and delivery system and Venus-A valve were removed after femoral artery was opened surgically, and repeated sheathless TAVR implantation was performed and was successful. Moderate aortic regurgitation occurred in 2 patients immediately after procedure, and trace or mild aortic regurgitation was detected in rest of the patients. One patient had puncture site rupture and bleeding after procedure, and was successfully treated by balloon compression without blood transfusion. Complete atrioventricular block occurred in 3 patients within 24 hours after procedure and lasted after 48-72 hours, permanent pacemakers were implanted in these patients. Conclusion: The sheathless transfemoral technique in TAVR is safe and feasible in severe aortic stenosis patients with small access vessel diameter.

[Observation on intestinal viral shedding time of hand, foot and mouth disease induced by coxsackievirus A6].

Objective: To observe the intestinal viral shedding time in patients with hand, food and mouth disease (HFMD) induced by coxsackievirus A6 (CA6). Method: Throat swab specimens and stool specimens of HFMD children were collected from those admitted to Hangzhou Children's Hospital between May and October 2015, while fluorescence quantitative PCR was used to detect the viral load.Eeighteen cases of HFMD children were followed up, who were confirmed as CA6 infection via laboratory tests.Stool specimen was collected every 4-7 days, and fluorescence PCR was used for virus nucleic acid detection until the stool viral nucleic acids of infected children turned to be negative.The intestinal virus shedding time of CA6-infected HFMD was compared with the intestinal virus shedding time of 65 children with enterovirus 71 (EV71) infection and 44 children with coxsackievirus A16 (CA16) infection of the previous studies (from May to September 2012). Result: The median stool viral load was 25×10(5) copies/ml (55×10(4) copies/mL, 9×10(6) copies/ml) in CA6-infected children.The numbers of stool virus nucleic acid turning negative were 0 case, 4 cases, 9 cases, 3 cases and 2 cases in 18 children at 1st, 2nd, 3rd, 4th, 5th weeks. At 5th week, the stool virus nucleic acid of children in CA6 group all turned to be negative.The positive rates of stool virus nucleic acid in EV71 group and CA16 group at the 5th week, however, were 31% and 27% respectively.There were statistically significant differences in distribution of positive rate of stool virus nucleic acid between CA6 infected children with EV71 and CA16 infected children (χ(2)=13.894, 10.698, P<0.05). Conclusion: The longest intestinal virus shedding time for CA6-infected HFMD children was 5 weeks, which is obviously shorter than that of EV71- infected children and CA16-infected children.

[The relationship among depression, anxiety, stress and addictive substance use behavior in 5 935 secondary vocational students].

Objective: To investigate the relationship among depression, anxiety, stress and addictive substance use behavior in secondary vocational students. Methods: Cluster sampling method and the Adolescent Health-related Behaviors Questionnaire were used to collect demographic characteristics, psychological symptoms, and addictive substance usage among 5 935 students in nine vocational schools in Chongqing, Zhaoqing, Ningbo, and Taiyuan. Multivariate logistic regression analysis was used to analyze the relationship between the addictive substance use behavior and psychological factors. Results: The detection rates of depression, anxiety and stress were 46.5% (n=2 762), 58.7% (n=3 483), and 29.8% (n= 1 770), respectively. The prevalence of addictive substances was 74.8% (n=4 440), traditional drugs was 0.8% (n=50), new drugs was 2.8% (n=166), other addictive drugs was 4.1% (n=241). Multivariate logistic regression analysis showed that compared with the normal psychological states of secondary vocational students, the OR value of mild depression tendency alcohol and tobacco use behavior of secondary vocational students was 1.45; the OR values of mild anxiety, moderate anxiety, severe anxiety and very serious anxiety were 1.46, 1.46, 1.71, and 1.83, respectively; the traditional drugs use behaviors were 5.51, and 2.61, respectively, for the severe anxiety and very serious anxiety. Compared with the normal psychological state of secondary vocational students, the OR values of the severe anxiety and very severe anxiety were 2.56, and 2.66, respectively, for severe anxiety and very serious anxiety. Compared with normal psychological status of secondary vocational students, the OR values of mild, moderate, severe, and very severe anxiety were 2.14, 2.47, 2.39, and 3.45, respectively; all P values <0.05. Conclusion: Anxiety and mild depression were risk factors of tobacco and alcohol use in secondary vocational students; severe and above anxiety were the risk factors of drug use in secondary vocational students; anxiety was the risk factor for other addictive drug use in secondary vocational students.

High-frequency repetitive transcranial magnetic stimulation over the left DLPFC for major depression: Session-dependent efficacy: A meta-analysis.

BACKGROUND: Depression is a major debilitating psychiatric disorder. Current antidepressant drugs are often associated with side effects or treatment resistance. The aim of this meta-analysis was to evaluate therapeutic effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in major depression (MD). METHODS: The medical data bases of PubMed, Medline, Embase and Cochrane Central Register were searched for randomized controlled trials (RCTs) reporting the therapeutic effects of high-frequency rTMS for depression, which were published in English between January 1990 and June 2016. The index terms were "depress*", "depression" and "transcranial magnetic stimulation". Depression outcome data of different sessions (5, 10, 15, and 20 sessions of rTMS treatment) were extracted and synthesized by calculating standardized mean difference (SMD) with 95% confidence intervals (CI) by using a random-effect model. Within each session group, the subgroup analyses based on the number of pulses (≤1000, 1200-1500, 1600-1800, and 2000-3000) were also conducted. RESULTS: Thirty RCTs with a total of 1754 subjects including 1136 in the rTMS group and 618 in the sham group were included in this meta-analysis. rTMS had a significant overall therapeutic effect on depression severity scores (SMD=-0.73, P<0.00001). The five, 10, 15, 20 sessions of rTMS treatments yielded the significant mean effect sizes of -0.43, -0.60, -1.13, and -2.74, respectively. In the four groups (5, 10, 15, 20 sessions), the maximal mean effect size was all obtained in the subgroup of 1200-1500 pulses per day (-0.97, -1.14, -1.91, -5.47; P<0.05). CONCLUSIONS: The increasing of HF-rTMS sessions is associated with the increased efficacy of HF-rTMS in reducing depressed patients' symptom severity. A total number of pulses of 1200-1500 per day appear to deliver the best antidepressant effects of HF-rTMS.

Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma.

Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.

[Impact of reduced left ventricular ejection fraction on all-cause mortality of 75 years old and over patients with moderate to severe aortic stenosis].

Objective: To evaluate the impact of left ventricular systolic dysfunction on all-cause mortality of 75 years old and over patients with moderate to severe aortic stenosis. Methods: Clinical data of 301 consecutive aged (≥75 years old) patients with a diagnosis of non-rheumatic moderate to severe aortic stenosis by echocardiography between January 1, 2008 and January 1, 2015 in our hospital were retrospectively analyzed. According to the LVEF, patients were divided into normal LVEF subjects and low LVEF subjects, and the low LVEF level was set at below 60%(≤60%(n=171)vs. >60%(n=130)), 55%(≤55%(n=101)vs. >55%(n=200)), 50%(≤50%(n=65)vs. >50%(n=236)), 45%(≤45%(n=51)vs. >45%(n=250)) and 40%(≤40%(n=37)vs. >40%(n=264)), respectively. All patients were followed to January 1, 2016.The primary end point was death from any cause. Log-rank test was used to compare the mortality between groups. Multivariate Cox regression model analysis was used to identify risk factors related to all-cause death. Results: The patients were followed-up 19 (8 to 37) months. The mortality was similar among the ≤60% and >60% groups(HR=0.741, 95%CI 0.457-1.201, P>0.05), but significantly difference was evidenced between the ≤55% and >55%(HR=0.524, 95%CI 0.329-0.836, P<0.01), ≤50% and >50%(HR=0.371, 95%CI 0.230-0.600, P<0.01), ≤45% and >45%(HR=0.343, 95%CI 0.208-0.564, P<0.01), ≤40% and >40% groups(HR=0.321, 95%CI 0.188-0.548, P<0.01). Among patients receiving conservative therapy, mortality was similar between ≤60% and >60% groups, but mortality was significantly lower in >55% group than in ≤55% group, in >50% group than in ≤50% group, in >45% group than in ≤45% group as well as in >40% group than in ≤40% group (all P<0.01). All-cause mortality was similar in patients treated with TAVR and/or SAVR. After adjusting for age, gender, chronic obstruct pulmonary disease, cerebrovascular disease, and aortic valve transaortic pressure gradient, multivariate Cox regression model analysis showed that patients in LVEF>55% group were associated with lower risk of all-cause mortality compared with≤55% group(HR=0.568, 95%CI 0.340-0.947, P<0.05). Conclusions: Among the 75 years old and over patients with moderate to severe aortic stenosis, LVEF≤55% is related to increased all-cause mortality and In TAVR and/or SAVR group, LVEF is not associated with all-cause mortality.

Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models.

Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro - in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds.

A novel variant of the ß-lactamase ADC-61 gene in multi-drug resistant Acinetobacter baumannii.

The aim of this study was to investigate the existence of a ß-lactamase gene in a group of multi-drug resistant Acinetobacter baumannii. Twenty strains of multi-drug resistant A. baumannii were isolated. Thirty-four ß-lactamase genes and the ISaba1-OXA-23 linkage were analyzed in these strains by polymerase chain reaction (PCR) and verified by DNA sequencing. Three kinds of ß-lactamase genes (TEM, ADC, and OXA-23) were identified, among which the sequence of strain No. 20, ADC, was different from ADC subtypes recorded by GenBank, and was identified as a new variant of ß-lactamase genes (named ADC-61 and registered in GenBank: accession No. JQ753702); all the other 19 strains were ADC-30. Eighteen strains of the OXA-23 group were all positive as indicated by detection of ISaba1-OXA-23 linkage. Gene sequencing indicated that the TEM gene was TEM-1. These results suggest that the three kinds of ß-lactamase genes identified in this study, TEM, ADC, and OXA-23, play a key role in drug resistance in this group of A. baumannii. To our knowledge, this is the first report of an emergent new mutation of the ß-lactamase gene, ADC-61, in China or abroad.