A randomized trial: The safety, pharmacokinetics and preliminary pharmacodynamics of ropivacaine oil delivery depot in healthy subjects.

INTRODUCTION: Ropivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects. METHODS: The abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block. RESULTS: Single-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 µg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h. CONCLUSIONS: RODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe. TRIAL REGISTRATION: Chictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.

Baseline lymphocyte and cholinesterase levels may be the predictors of chronic herbal drug-induced liver injury.

Objective: To investigate the factors influencing the chronicity of drug-induced liver injury (DILI) caused by Chinese herbal medicine. Methods: Patients with DILI diagnosed by using the RUCAM score were enrolled retrospectively. The subjects were patients with DILI induced by taking Chinese herbal medicine and were followed up for 48 weeks. These patients were divided into a cure group and a chronic group. The biochemical indicators were monitored at baseline and every 3 months. Logistic regression was used to analyze the risk factors of DILI chronicity. The ROC (receiver operator characteristic) curve was used to analyze the diagnostic efficiency of each factor. Results: A total of 420 patients with DILI were enrolled; 122 of them were caused by Chinese herbal medicine, 70.5% (86/122) of them were female, chronic group 31.2% (39/122), and cure group 68.0% (83/122); cholinesterase (ChE) in the chronic group was lower than that in the cure group (5467.10 ± 2010.40 U/L vs. 6248.52 ± 1901.78 U/L, p = 0.04, t = 2.078). There was no significant difference in the age between cured patients and chronic patients (p = 0.156, Z = -1.417). There was no significant difference between the prognosis of different genders (p = 0.521, Z = -0.639). The logistic regression analysis showed that baseline lymphocyte (OR = 0.429, 95%CI = 0.205-0.898, p = 0.025) and cholinesterase (OR = 0.088, 95%CI = 0.008-0.994, p = 0.049) were independent risk factors of drug-induced chronicity. Conclusion: Baseline lymphocyte and cholinesterase may be the predictive factors for the chronicity of Chinese herbal medicine-induced liver injury.

Changes in the Cytokine Profiles of Patients with Chronic Hepatitis B during Antiviral Therapy.

OBJECTIVE: To investigate the changes in the cytokine profiles of chronic hepatitis B (CHB) patients undergoing antiviral treatment. METHODS: Hepatitis B e antigen (HBeAg)-positive patients were treated with Pegylated interferon (PEG-IFN) and entecavir (ETV). Clinical biochemistry and cytokines were detected at baseline and every 3 months. RESULTS: In all, 200 patients completed 48 weeks of treatment, 100 in the PEG-IFN group and 100 in the ETV group. During 3-6 months of treatment, compared with baseline, the PEG-IFN group showed a significant decrease in interferon-gamma (IFN-γ), interleukin-17A (IL-17A), interleukin-6(IL-6), interleukin-10(IL-10), and transforming growth factor beta (TGF-ß) ( P < 0.001) and a significant increase in interferon-alpha 2(IFN-α2) ( P < 0.001). In the ETV group, IL-10 and TGF-ß1 decreased significantly ( P < 0.001). After 3 months, the levels of IFN-α2, IL-17A, and tumor necrosis factor-alpha(TNF-α) in the PEG-IFN group were significantly higher than those in the ETV group ( P < 0.01). The levels of IL-6 and TGF-ß3 were significantly lower than those in the ETV group ( P < 0.01). After 6 months, the levels of IFN-α2, IFN-γ, and TNF-α in the PEG-IFN group were significantly higher than those in the ETV group ( P < 0.01), while the levels of IL-6 and TGF-ß3 were significantly lower than those in the ETV group ( P < 0.01). Compared with ETV, PEG-IFN had higher HBeAg and HBsAg disappearance rates. CONCLUSION: During antiviral therapy, a change in the cytokine profile occurred; in the aspect of immune control and functional cure, PEG-IFN was significantly better than ETV.

An Insight of the First Community Infected COVID-19 Patient in Beijing by Imported Case: Role of Deep Learning-Assisted CT Diagnosis.

In the era of coronavirus disease 2019 (COVID-19) pandemic, imported COVID-19 cases pose great challenges to many countries. Chest CT examination is considered to be complementary to nucleic acid test for COVID-19 detection and diagnosis. We report the first community infected COVID-19 patient by an imported case in Beijing, which manifested as nodular lesions on chest CT imaging at the early stage. Deep Learning (DL)-based diagnostic systems quantitatively monitored the progress of pulmonary lesions in 6 days and timely made alert for suspected pneumonia, so that prompt medical isolation was taken. The patient was confirmed as COVID-19 case after nucleic acid test, for which the community transmission was prevented timely. The roles of DL-assisted diagnosis in helping radiologists screening suspected COVID cases were discussed.

Emergence of community-acquired adenovirus type 55 as a cause of community-onset pneumonia.

BACKGROUND: Since 2008, severe cases of emerging human adenovirus (HAdV) type 55 (HAdV-55) were reported sporadically in China. But no comparative studies had been conducted to discern the differences in epidemiologic and clinical abnormalities between HAdV-55 and other types (HAdV-7, HAdV-3, HAdV-14, HAdV-50, and HAdV-C). METHODS: A multicenter surveillance study for adult and adolescent community-acquired pneumonia (CAP) was conducted prospectively in Beijing and Yan Tai between November 2010 and April 2012. A standardized data form was used to record clinical information. The viral DNA extracted from the clinical samples or adenovirus viral isolates was sequenced. RESULTS: Among 969 cases, 48 (5%) were identified as adenovirus pneumonia. Six branches were clustered: HAdV-55 in 21, HAdV-7 in 11, HAdV-3 in nine, HAdV-14 in four, HAdV-50 in two, and HAdV-C in one. Most HAdV-55 cases were identified during February and March. All the hypervariable regions of the hexon genes of the 21 HAdV-55 strains were completely identical. Patients who had HAdV-55 were about 10 years older ( P = .027) and had higher pneumonia severity index scores ( P = .030) compared with those with other types (HAdV-7, HAdV-3, HAdV-14, HAdV-50, and HAdV-C). Systemic BP was also higher among patients in the HAdV-55 group ( P = .006). Unilateral or bilateral consolidations were the most common radiologic findings in both patients with HAdV-55 and those with other types (57.9% vs 36%). More than one-half of the patients were admitted to hospital; oxygen therapy was given to 29.2% of the 48 patients, and two needed mechanical ventilation. CONCLUSIONS: HAdV-55 has established itself as a major pneumonia pathogen in the Chinese population, and further surveillance and monitoring of this agent as a cause of CAP is warranted.

[Etiologic characteristics of adult patients with community-acquired pneumonia in Beijing].

OBJECTIVE: To explore the etiologic characteristics of adult patients with community-acquired pneumonia (CAP) in Beijing. METHODS: A multicenter cohort of 510 adult CAP patients were enrolled from Beijing during the period of November 2010 to May 2012. Multiplex polymerase chain reaction (PCR), real-time fluorescence quantitative PCR and legionella urinary antigen were used to detect common respiratory viruses, Mycoplasma pneumoniae and legionella respectively. Bacteria were detected by sputum culture, blood culture and Streptococcus pneumoniae urinary antigen. Statistical analyses were performed for the etiologic characteristics and seasonal distribution of detected pathogens. RESULTS: Pathogens were detected in 240/500 (47.1%) study patients. The mixed infection of different pathogens was present in 42 cases (8.2%), viruses in 164 (32.2%), Mycoplasma pneumoniae in 91 (17.8%), bacteria in 26 (5.1%) and Legionella in 3 (0.6%). Among 164 patients infected with viruses, 194 viral strains were detected. Influenza virus represented the greatest proportion with 105 (54.1%) in viral infections. Between November 2010 to October 2011, Influenza A infections increased gradually in November 2010, peaked in February 2011 and declined by March 2011 in China. Mycoplasma pneumoniae was predominant in winter and spring. CONCLUSIONS: There is a high detection rate of virus and Mycoplasma pneumoniae in adult CAP patients in Beijing. And more consideration should be given to influenza virus and Mycoplasma pneumoniae infections in winter and early spring.

An uncontrolled open-label, multicenter study to monitor the antiviral activity and safety of inhaled zanamivir (as Rotadisk via Diskhaler device) among Chinese adolescents and adults with influenza-like illness.

BACKGROUND: It is the first multicenter clinical study in China to investigate zanamivir use among Chinese adolescents and adults with influenza-like illness (ILI) since 2009, when inhaled zanamivir (RELENZA(®)) was marketed in China. METHODS: An uncontrolled open-label, multicentre study to evaluate the antiviral activity, and safety of inhaled zanamivir (as Rotadisk via Diskhaler device); 10 mg administered twice daily for 5 days in subjects ≥ 12 years old with ILI. Patients were enrolled within 48 hours of onset and followed for eight days. Patients were defined as being influenza-positive if the real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) test had positive results. RESULTS: A total of 400 patients ≥ 12 years old were screened from 11 centers in seven provinces from March 2010 to January 2011. Three hundred and ninety-two patients who took at least one dose of zanamivir were entered into the safety analysis. The mean age was 33.8 years and 50% were male. Cardiovascular diseases and diabetes were the most common comorbidities. All the reported adverse events, such as rash, nasal ache, muscle ache, nausea, diarrhea, headache, occurred in less than 1% of subjects. Mild sinus bradycadia or arrhythmia occurred in four subjects (1%). Most of the adverse events were mild and did not require any change of treatment. No severe adverse events (SAE) or fatal cases were reported. Bronchospasm was found in a 38 years old woman whose symptoms disappeared after stopping zanamivir and without additional treatment. All the 61 influenza virus isolates (43 before enrollment, 18 during treatment) proved to be sensitive to zanamivir. CONCLUSIONS: Zanamivir is well tolerated by Chinese adolescents and adults with ILIs. There is no evidence for the emergence of drug-resistant isolates during treatment with zanamivir.

Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial.

BACKGROUND: Observational studies from Asia suggest that maxingshigan-yinqiaosan may be effective in the treatment of acute H1N1 influenza. OBJECTIVE: To compare the efficacy and safety of oseltamivir and maxingshigan-yinqiaosan in treating uncomplicated H1N1 influenza. DESIGN: Prospective, nonblinded, randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00935194) SETTING: Eleven hospitals from 4 provinces in China. PATIENTS: 410 persons [corrected] aged 15 to 69 [corrected] years with laboratory-confirmed H1N1 influenza. INTERVENTION: Oseltamivir, 75 mg twice daily; maxingshigan-yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan-yinqiaosan; or no intervention (control). Interventions and control were given for 5 days. MEASUREMENTS: Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction. RESULTS: Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan-yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan-yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan-yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan-yinqiaosan reported nausea and vomiting. LIMITATIONS: Participants were young and had mild H1N1 influenza virus infection. Missing viral data precluded definitive conclusions about viral shedding. CONCLUSION: Oseltamivir and maxingshigan-yinqiaosan, alone and in combination, reduced time to fever resolution in patients with H1N1 influenza virus infection. These data suggest that maxingshigan-yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection. PRIMARY FUNDING SOURCE: Beijing Science and Technology Project and Beijing Nova Program.

Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside/nucleotide analogue treatment among Chinese chronic hepatitis B patients.

BACKGROUND: Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs). METHODS: Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250. RESULTS: Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively (P<0.01). CONCLUSIONS: One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.

Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naïve Chinese patients.

Full-length hepatitis B virus (HBV) reverse transcriptase (RT) sequences were amplified and sequenced among 192 nucleos(t)ide analogue (NA)-naïve Chinese patients with chronic hepatitis B. Deduced amino acids (AAs) at 42 previously reported potential NA resistance (NAr) mutation positions in RT region were analyzed. Patients were found with either B-genotype (28.65%) or C-genotype (71.35%) infections. Rt53, rt91, rt124, rt134, rt221, rt224, rt238 and rt256 were identified as B- and C-genotype-dependent polymorphic AA positions. AA substitutions at 11 classical NAr mutation positions, i.e. rt80, rt169, rt173, rt180, rt181, rt184, rt194, rt202, rt204, rt236 and rt250, were not detected. However, potential NAr mutations were found in 30.73% (59/192) isolates, which involved 18 positions including rt53, rt207, rt229, rt238 and rt256, etc. The concomitant AA changes of HBsAg occurred in 16.67% (32/192) isolates including sG145R mutation. One-third of mutation positions were located in functional RT domains (e.g. rt207 and rt233), A-B interdomains (overlapping HBsAg 'a' determinant and showing most concomitant immune-associated mutations) and non-A-B interdomains (e.g. rt191 and rt213), respectively. Genotypes B and C each showed several preferred positions to mutate. These results might provide insights into understanding the evolution and selection basis of NAr HBV strains under antiviral therapy.

[Randomized controlled observation on head point-through-point therapy for treatment of insomnia].

OBJECTIVE: To observe the therapeutic effect of head point-through-point therapy on insomnia and to probe the mechanism. METHODS: Seventy-one cases of insomnia were randomly divided into a head penetration needling group (n=36) and a routine acupuncture group (n=35). In the head penetration needling group, Shenting (GV 24)-through-anterior Shencong (EX-HN 1), bilateral Toulinqi (GB 15)-through-bilateral Shencong (EX-HN 1), posterior Shencong-through-Qiangjian (GV 18) were selected; and in the routine acupuncture group, Baihui (CV 20), Yintang (EX-HN 3), Sishencong (EX-HN 1), Neiguan (PC 6), etc. were selected. After treatment of 30 days, their therapeutic effects, cumulative scores of Pittsburgh Sleep Quality Index (PSQI) and plasma serotonin contents before and after treatment were compared. Results The total effective rate of 91.7% in the head penetration needling group was better than 77.1% in the routine acupuncture group (P < 0.05), and the improvement of sleep quality, falling asleep time and the total cumulative score of PSQI in the head penetration needling group was superior to that in the routine acupuncture group (P < 0.05), and plasma serotonin was significantly increased in the head penetration needling group with a significant difference as compared with that in the routine acupuncture group (P < 0.05). CONCLUSION: The therapeutic effect of head penetration needling is better than that of the routine acupuncture, and the mechanism is related with regulation of serotonin metabolism.

[Clinical observation on head point-through-point electroacupuncture for treatment of poststroke depression].

OBJECTIVE: To observe clinical therapeutic effect of head point-through-point electroacupuncture (EA) on poststroke depression (PSD) and to study the mechanism. METHODS: One hundred and eight cases of PSD were randomly divided into a point-through-point EA group (n = 38), a non point-through-point group (n = 36) and a western medicine group (n = 34). After treatment of 28 days, their therapeutic effects, scores of HAMD depression scale and SDS self-rating scale, and plasma 5-HT contents were compared before and after treatment among the 3 groups. RESULTS: The effective rate of 86.84% in the point-through-point EA group was better than 63.89% in the non point-through-point group and 67.65% in the western medicine group (P < 0.05 or P < 0.01). Plasma 5-HT content in the point-through-point EA group increased significantly, with a very significant difference as compared with that of the non point-through-point group (P < 0.01). CONCLUSION: Head point-through-point therapy can obviously increase plasma 5-HT content of the patient with PSD, so as to cure poststroke depression, with a better therapeutic effect than other two groups.

[Difference and significance of T-lymphocyte subsets in differential diagnosis between severe acute respiratory syndrome and common atypical pneumonia].

BACKGROUND: To clarify the difference and significance of T-lymphocyte subsets in differential diagnosis between severe acute respiratory syndrome SARS) and common atypical pneumonia. METHODS: Totally 100 patients hospitalized in Beijing Ditan Hospital since March to June 2003 with clinical diagnosis of SARS were involved in this study. These patients courses of disease were over 3 weeks. These patients were divided into two groups, SARS group and common atypical pneumonia group (non-SARS group). The counts of CD3+, CD4+ and CD8+ T-lymphocyte of two groups were systematically recorded and analyzed. RESULTS: Sixty-five of the patients were confirmed to have common type of SARS, including 26 males and 39 females, 50 cases received methylprednisolone treatment. Thirty-five cases had common atypical pneumonia (non-SARS), 21 were males while 14 were females, 20 cases received methylprednisolone treatment. All the cases of two groups were cured in the end. The SARS patients T-lymphocyte counts decreased first and then increased. Before 15 days of disease course, mean CD3+, CD4+, CD8+ T-lymphocyte counts of SARS patients were decreased apparently (694+/-568/microl, 441+/-356/microl, 309+/-462/microl). After 15th day of disease course, the counts gradually returned to normal CD3+, CD4+, CD8+ T-lymphocyte counts of non-SARS patients were normal. Compared with patients of the same group who were not treated with glucocorticoids, T-lymphocyte counts of non-SARS patients treated with glucocorticoids had no obvious difference. But glucocorticoids had some effect on SARS patients recovery of cellular immune function, i.e., it delayed the recovery by about 6 days. CONCLUSION: With or without treatment with glucocorticoids,the lowered CD3+, CD4+, CD8+ T-lymphocyte counts in the early stage are of very important significance in differential diagnosis between severe acute respiratory syndrome and common atypical pneumonia.