[The association between baseline TPOAb and/or TgAb positivity and thyroid immune-related adverse events in patients with malignancies following treatment with immune checkpoint inhibitors].

Objective: To investigate the association between positive anti-thyroid peroxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb) and the occurrence of thyroid immune-related adverse events (irAEs) in patients with malignant tumors who treated with immune checkpoint inhibitors (ICIs). Methods: A case-control study. A total of 116 patients with malignant tumor who received ICIs treatment and underwent thyroid function evaluation at Peking Union Medical College Hospital from January 2017 to April 2023 were enrolled retrospectively, including 77 males and 39 females, with a median age of (M(Q1, Q3)) 63.0 (55.0, 70.0) years. The patients were divided into the euthyroid group (n=58) and the thyroid irAEs group (n=58) according to whether thyroid irAEs occurred after ICIs treatment. The clinical characteristics and baseline anti-thyroid antibodies associated with the occurrence of thyroid irAEs after ICIs treatment in patients with malignant tumors were evaluated. Variables with statistical significance in univariate analysis were included in multivariate logistic regression model to analyze the risk factors for thyroid irAEs in patients with malignant tumors who received ICIs treatment. Results: In irAEs group, therewore 4 (3.4%) cases of clinical thyrotoxicosis, 23(19.8%) cases of subclinical thyrotoxicosis, 23 (19.8%) cases of clinical hypothyroidism, and 8(6.9%) cases of subclinical hypothyroidism. The positive rate of anti-thyroid antibodies at baseline in the thyrioid irAEs group was higher than that in the euthyroid group［16/58（27.6%）vs 3/58（5.2%），P=0.001］. After at least one course of ICIs treatment, the incidence of thyroid irAEs in patients with positive anti-thyroid antibodies at baseline was 84.2% (16/19), whereas it was 43.3% (42/97) in patients with negative anti-thyroid antibodies(P=0.001). Univariate logistic regression analysis showed that gender (OR=2.812, 95%CI:1.257-6.293), baseline thyroid autoantibodies were positive (OR=6.984, 95%CI: 1.909-25.547), baseline TgAb positivity (OR=8.909, 95%CI: 1.923-41.280), and baseline TPOAb positivity (OR=7.304, 95%CI: 1.555-34.308) were associated with thyroid irAEs (all P<0.05). Multivariate logistic regression analysis indicated that baseline TgAb positivity (OR=7.637, 95%CI: 1.617-36.072) was a risk factor for thyroid irAEs (P=0.01). Conclusions: The incidence of thyroid irAEs is higher in patients who are positive for baseline TPOAb and/or TgAb compared to those who are negative for TPOAb and TgAb. Patients with positive TgAb at baseline are at high risk of developing thyroid irAEs.

[Exploration and contemplation of homogenized education of specialists in pulmonary and critical care medicine at member hospitals of a hospital consortium].

Talent construction is the cornerstone to the establishment of a high-quality, homogeneous healthcare system in a healthcare consortium. Pulmonary and critical care medicine (PCCM) as the first pilot specialty, the standardized training of PCCM specialists has started and achieved remarkable results. The consortium member hospitals' physician specialist education is an important complement to PCCM training. The establishment of the consortium provides a new form of the education of physicians in PCCM, with the advantages of high quality teaching, wide coverage of staff and throughout the career development process. This article summarized the current status of physician specialty education in the member hospitals of the consortium, and further proposes the goal of homogenized specialty education for physicians in the member hospitals. And it analyzed in depth the problems that existed in the practice of training for hospital consortium member hospitals specialists, such as non-uniform level of instruction, non-systematic content of training, limited sources of teaching cases, and lack of teaching materials and equipment. For the medical consortium member hospital physician specialty education of in-depth thinking, we put forward the corresponding countermeasures. The aim of this study is to explore the homogenization of the specialty education system of pulmonary and critical care medicine in the member hospitals, in order to comprehensively improve the medical level of respiratory specialists in the member hospitals of the medical consortium.

[Clinical analysis of COVID-19 in patients with preexisting interstitial lung abnormalities].

Objective: To describe the clinical characteristics of SARS-CoV-2 infected patients with interstitial lung abnormalities (ILA) during the COVID-19 pandemic. Methods: We respectively enrolled ILA patients who had been regularly followed up in Peking Union Medical College Hospital for more than six months since January 2021. Clinical data of these ILA patients were collected after the outbreak of COVID-19 pandemic (from December 2022 to January 2023), thirty-eight patients with preexisting ILA were enrolled. Among them, there were 34 ILA patients (20 males and 14 females) who were infected with SARS-CoV-2 during this period, with an average age of (64.0±8.8) years old (range: 41-80). There were 12 (35.3%) ILA patients who were suffered from COVID-19(pneumonia group) and others were the non-pneumonia group. The clinical characteristics, including vaccination status, features of COVID-19 and outcomes of the two groups were compared. Results: Regarding the subcategories of ILA, there were 7 cases of subpleural fibrotic ILA, 10 cases of subpleural non-fibrotic ILA, and 17 cases of non-subpleural ILA. Before SARS-CoV-2 infection, the average pulse oxygen saturation at rest was (97.38±0.87)% (range: 96%-99%); average forced vital capacity (FVC) was (97.6±18.1)% predicted (range: 65%-132%); and average diffusion capacity for carbon monoxide (DLCO) was (76.2±16.3)% predicted (range: 53%-108%). Nineteen patients had been vaccinated with 3 doses of SARS-CoV-2 vaccines, and 5 of them developed COVID-19. One patient had received one dose of vaccine and did not develop COVID-19. The other 14 patients had not been vaccinated, and seven of them developed COVID-19. Of the 12 patients with COVID-19, six were diagnosed with severe COVID-19, and the other 6 ILA patients were diagnosed with moderate COVID-19. Among them, 1 patient was complicated by deep vein thrombosis of left lower limb. All 6 patients with severe COVID-19 who were cured after systemic corticosteroids. As for the other six moderate COVID-19 patients, all were cured and/or improved greatly: two were treated with short-term oral corticosteroids, one was prescribed a dose of compound betamethasone, and the other two were not treated with systemic corticosteroids. Conclusion: Patients with ILA were predisposed to develop COVID-19 after infection with SARS-CoV-2, and more than half of them had severe COVID-19.

[Clinical characteristics and prognosis analysis of pulmonary sarcomatoid carcinoma].

Objective: To summarize the clinical characteristics, treatment, and outcomes of patients with pulmonary sarcomatoid carcinoma (PSC) in order to improve clinicians' understanding of this disease. Methods: The clinical data of patients diagnosed with PSC in our hospital from January 1, 2015 to November 30, 2023 were retrospectively analyzed. According to whether radical resection was performed, the patients were divided into resectable group and unresectable group. The characteristics and treatments of PSC in different groups were compared. The survival curves were drawn by Kaplan-Meier method to compare the prognosis of different groups of patients. Results: A total of 43 PSC patients were included, including 32 males, with an average age of (62.79±9.59) years, and 31 smokers. Peripheral-type tumors were more common, with imaging showing predominantly solid soft tissue masses, and the maximum diameter of the tumor was more than 5 cm in 14 patients. Among the 23 patients who underwent NGS gene testing, the KRAS mutation rate was 43.5%, the TP53 mutation rate was 30.4%, and the MET mutation rate was 8.7%, all of which were MET-14 exon skipping mutations. PD-L1 expression was detected in 13 patients, 10 of whom showed high expression. The median overall survival (mOS) of the 43 patients with PSC was 24.6 months (13.0-52.7 months). Among them, 22 patients underwent radical lobectomy plus mediastinal lymph node dissection, 13 patients had postoperative recurrence, and 7 patients died during follow-up. The median disease-free survival (mDFS) was 12.3 months, the mOS was not achieved and the 1-year OS rate was 77.3 %. Twenty-one patients had unresectable locally advanced or advanced stage, and 15 patients died. The mDFS was 2.5 months, the mOS was 6.2 months, and the 1-year OS rate was 42.9 %. Seventeen patients received immunotherapy, and 1 patient received targeted therapy with the MET inhibitor glumetinib. Conclusions: PSC has a higher incidence in the elderly, smokers, and males, is highly malignant and has a poor prognosis. Based on its molecular biological characteristics, PD-L1 expression and tumor molecular detection can be performed to guide treatment options.

[Clinical features and prognostic analysis of checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer].

Objective: To describe the clinical characteristics of patients with non-small cell lung cancer (NSCLC) who developed checkpoint inhibitor pneumonitis (CIP) and to explore potential prognostic factors. Methods: NSCLC patients who were complicated with CIP after immune checkpoint inhibitors (ICIs) therapy in our institute were enrolled in this study from 1 July 2018 to 30 November 2022. Clinical data of NSCLC-CIP patients were collected, including clinical and radiological features and their outcomes. Results: Among the 70 enrolled NSCLC-CIP patients, there were 57 males (81%) and 13 females (19%). The mean age at the diagnosis of CIP was (65.2±6.3) years. There were 46 smokers (66%), 26 patients (37%) with emphysema, 19 patients (27%) with previous interstitial lung disease, and 26 patients (37%) with a history of thoracic radiation. The mean interval from the first application of checkpoint inhibitor to the onset of CIP was (122.7±106.9) days (range: 2-458 days). The main chest CT manifestations were coincided with non-specific interstitial pneumonia (NSIP) pattern and organizing pneumonia (OP) pattern. Most patients had grade 2 (21 cases) or grade 3 (34 cases) CIP. Seventeen patients had been concurrent with other immune-related adverse events such as rash, hepatitis, colitis, and thyroiditis. Half of the enrolled patients (36 patients/51%) had fever, and most patients had elevated C-reactive protein (52 patients/72%) and all patients had elevated erythrocyte sedimentation rate (70 patients/100%). Serum lactate dehydrogenase was elevated in 34 CIP patients. Prednisone≥1 mg·kg-1·d-1 (or equivalent) was the most commonly used initial treatment in CIP patients (50 patients/71.4%). Complications with pulmonary infections (OR=4.44, P=0.03), use of anti-fungal drugs (OR=5.10, P=0.03) or therapeutic dose of sulfamethoxazole (OR=4.86, P=0.04), longer duration of prednisone≥1 mg·kg-1·d-1 (or equivalent) (Z=-2.33, P=0.02) were probable potential risk factors for poor prognosis. Conclusions: Older males with smoking history might be predisposed to develop NSCLC-CIPs after ICIs therapy. NSIP pattern and OP pattern were common chest CT manifestations. Complications with pulmonary infections (especially fungal infection or Pneumocystis jirovecii pneumonia), longer duration, longer duration of high-dose corticosteroids were likely potential risk factors for poor prognosis.

[Clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors].

Objective: Cancer immunotherapy can lead to various side effects, termed immune-related adverse events (irAE). This study summarized and analyzed the clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI). Methods: This is a retrospective case series study involving 11 patients diagnosed with ILICI at the Peking Union Medical College Hospital from November 2019 to November 2021. Patient demographic information and clinical data, including gender, age, ILICI onset, clinical and radiological manifestations, pathological features, treatment, and resumption of ICI were retrospectively collected and analyzed. Results: The patients were primarily males (9/11) with a median age of 65 (range: 32-73) years. ICI mainly resulted in either partial remission (4/11) or stable disease (3/11). ILICI occurred after a median of two cycles of anti-programmed cell death-1 (PD-1) therapy, with a median time from the initial and last anti-PD-1 therapy to ILICI onset of 57 days and 17 days, respectively. ILICI was mostly severe (3/11) or very severe (6/11). While the clinical and radiological manifestations were non-specific, the pathological features were active lobular hepatitis and portal inflammation, with prominent CD8+T lymphocyte infiltration. The basic treatment was hepatoprotective drugs (10/11). Glucocorticoids were used as the primary therapy (9/11) but were ineffective in 4 of 9 cases. Of these, 3 of 9 cases received combined treatment with mycophenolate mofetil (MMF), only one of whom achieved remission. By the end of the study, 2 of 11 cases had resumed ICI and neither had experienced an ILICI relapse. Conclusion: The ILICI patients in this study had a corresponding history of ICI treatment and pathological features. The main treatment included hepatoprotective drugs and glucocorticoids. Immunosuppressive drugs were added for some cases but had poor efficacy.

[Comparison of the therapeutic effects of optic nerve sheath fenestration and medication on papilledema due to cerebral venous thrombosis].

Objective: To compare the therapeutic effects of optic nerve sheath fenestration (ONSF) and medication on papilledema induced by cerebral venous thrombosis (CVT). Methods: Patients with papilledema induced by CVT in Beijing Tiantan Hospital and Xuanwu Hospital from January 2017 to July 2022 were retrospectively enrolled and were divided into two groups according to the treatment strategies they underwent, with 76 cases (107 eyes) in ONSF group and 35 cases (69 eyes) in medication group. The degree of papilledema was evaluated by the modified Frisén's grading (grade 0-1 was defined as mild, grade 2-3 was moderate, and grade 4-5 was severe edema). The mean defect (MD) of visual field, the degree of papilledema, and the mean retinal nerve fiber layer (RNFL) thickness in different subgroups were compared between baseline versus 1 month after ONSF or medication. Results: There were 76 cases in ONSF group (26 males and 50 females), and aged (35.3±11.4) years. Meanwhile, there were 35 cases in medication group (22 males and 13 females), and aged (35.2±11.0) years. Compared with baseline, MD were improved in both moderate [(-8.4±6.6) vs (-11.8±8.6) db, P=0.021] and severe [(-8.1±5.3) vs (-11.4±6.9) db, P<0.001] papilledema subgroups after ONSF, while there was an improvement in mild papilledema subgroup [(-1.5±5.3) vs (-3.4±5.1) db, P<0.001] after medication. The papilledema (Frisén's scores) in both ONSF group (P<0.001) and medication group (P=0.010) was improved. Compared with baseline, the mean RNFL decreased in mild [(78.5±13.5) vs (91.0±17.4) µm, P=0.002], moderate [(126.6±67.6) vs (154.8±77.9) µm, P=0.011] and severe [(179.0±70.9) vs (230.6±89.7) µm, P=0.001] papilledema subgroups after ONSF, while the mean RNFL decreased [(142.0±29.3) vs (158.8±22.7) µm, P=0.020] in moderate papilledema subgroup after medication. Conclusions: ONSF might attenuate CVT-mediated papilledema, and improve the visual function in patients with moderate and severe papilledema. Likewise, patients with mild papilledema could also get benefit from medication.

[Establish a whole-process comprehensive surveillance management mode for immune checkpoint inhibitor pneumonitis].

The application of immune checkpoint inhibitors (ICIs) has shown impressive anti-tumor efficacy across multiple malignant tumors, leading to the prolonged survival period of tumor patients. However, immune-related adverse events should not be ignored. Checkpoint inhibitor pneumonitis (CIP) is a pulmonary adverse event that can occur in malignant tumor patients after receiving ICIs treatment. The incidence of CIP has been reported to range from 2.7% to 20.0% in clinical trials and real-world research. Furthermore, some patients might suffer from serious or fatal CIP, and the prognosis of such patients will be poor. Early detection, diagnosis and treatment may improve the prognosis of these patients. The establishment of a whole-process CIP comprehensive surveillance management mode covering the health care system and patients during ICIs treatment might be helpful to improve the early diagnosis and treatment capacity of CIP, which is a key measure to improve the prognosis of these patients.

[Effects of one-stop hybrid operation on the risk and prognosis of brain arteriovenous malformations with posterior feeding artery].

Objective: To explore the effect of the combination of posterior circulation embolization and micro-resection on the risk and prognosis in patients with brain arteriovenous malformations (bAVMs) supplied by posterior circulation in a one-stop hybrid operation setting. Methods: Patients with bAVMs supplied by posterior circulation who received surgical treatment in Beijing Tiantan Hospital, Capital Medical University, were enrolled from January 2016 to December 2019 from a prospective, multicentral cohort (NCT03209804). The patients were divided into the posterior circulation embolization group and the non-posterior circulation embolization group. Propensity score matching (PSM) (1∶1) was performed according to the baseline information, the morphology of bAVMs, vascular architecture, and Spetzler-Martin grade of brain lesions. The primary endpoint was the deterioration of neurological function. The secondary endpoints were perioperative complications. The differences in surgical risk and clinical prognosis between the two groups were compared. Results: Five hundred and forty-five patients were enrolled in the cohort, and 38.3% met the included criteria (n=209 cases), with 42 cases in the posterior circulation embolization group and 167 cases in the non-posterior circulation embolization group. Depending on whether the patients were posterior circulation embolized, 39 patients in the posterior circulation embolization group and 39 patients in the non-posterior circulation embolization group were finally included after performing PSM. There were 50 males and 28 females, aged 5-58 (30±13) years. The exacerbation rate of neurological dysfunction in the posterior circulation embolization group was higher than that in the non-posterior circulation embolization group three months after surgery, however there was no statistically significant difference between the two groups [15.4% (6/39) vs 2.6% (1/39), P=0.107]. The intraoperative blood loss in the embolization group was significantly less than that in the non-embolization group [650 (500, 1 500) ml vs 1 200 (800, 2 000) ml, P=0.002]. There was no significant difference in microsurgery time between the two groups [437 (374, 521) min vs 424 (359, 601) min, P=0.865]. Likewise, there were no statistically significant differences in the incidence of postoperative complications and aggravation of neurological dysfunction, including postoperative bAVMs residual [5.1%(2/39) vs 7.7%(3/39), P=1.000], hemorrhagic complications [5.1%(2/39) vs 0(0), P=0.494], postoperative ischemic complications [10.3%(4/39) vs 5.1%(2/39), P=0.675], neurological dysfunction at discharge (17.9% vs 15.4%, P=0.755), and one-year neurological dysfunction [5.1%(2/39) vs 2.6%(1/39), P=1.000]. Conclusions: Posterior circulation embolization of bAVMs in a one-stop hybrid operation can effectively reduce intraoperative bleeding and surgical risk. Embolization of the feeding artery has no significant impact on the perioperative complications and neurological outcomes.

[Diagnostic value of surgical lung biopsies for diffuse parenchymal lung disease: the change of disease spectrum in the past 28 years in a single institution in China].

Objective: To investigate the changes of disease spectrum in diffuse parenchymal lung disease (DPLD) diagnosed by surgical lung biopsy, and to explore the diagnostic value of surgical lung biopsy in DPLD. Methods: Four hundred and fifty-five consecutive DPLD patients, who underwent surgical lung biopsy in Peking Union Medical College Hospital during the past 28 years, were analyzed retrospectively. Results: There were 211 males and 244 females. The average age at biopsy was (45±14) years. Four hundred and eleven cases (90.3%) were diagnosed by pathologic findings. Four hundred and forty-one cases (96.9%) were diagnosed by clinical-radiologic-pathologic multidisciplinary discussion. The 30-day mortality and 90-day mortality were 2.4% and 3.3% respectively. The disease spectrum included interstitial pneumonia in 209 cases (45.9%) (nonspecific interstitial pneumonia in 105 cases, usual interstitial pneumonia in 33 cases), other miscellaneous DPLD in 166 cases (36.5%) (including hypersensitivity pneumonitis in 49 cases), tumor in 39 cases (8.6%), and infectious diseases in 27 cases (5.9%). In the three consecutive periods (1993-2002, 2003-2012 and 2013-2020), the number of biopsies was 76 (16.7%), 297 (65.3%) and 82 (18%) respectively. The disease spectrum changes over time: in the above three periods, the percentage of interstitial pneumonia in DPLD was 68.4%, 45.1% and 28%, other miscellaneous DPLDs were 22.4%, 39.4% and 39.0%, the tumors were 2.6%, 7.4% and 18.3%, the infectious diseases were 5.3%, 5.1% and 9.8%. Conclusions: This study presented the changes of disease spectrum in DPLD diagnosed by surgical lung biopsy through single center real-world data, reflecting the progress of clinicians' understanding of DPLD and interstitial pneumonia. Surgical lung biopsy is still valuable for some difficult and complicated DPLD cases.

[Effects of ambient particulate matter (PM10) on prevalence of diabetes and fasting plasma glucose].

Objective: To explore the effect of long-term exposure to ambient particulate matter (PM10) on the prevalence of diabetes and fasting plasma glucose (FPG). Methods: The subjects of the study were from the baseline population of "Jinchang Cohort", and 24 285 subjects were finally included after excluding incomplete home address information and diabetic diagnosis information. The demographic characteristics, lifestyle and health status of the survey subjects were collected through questionnaire, physical examination and laboratory tests. ArcGIS software was used to match the nearest environmental monitoring stations for each subject according to residential address. Two-year average concentrations of PM10 were calculated to estimate exposure level. The logistic regression and the multiple linear regression were conducted to assess the effects of ambient PM10 on the prevalence of diabetes and FPG. The restricted cubic spline was used to quantify the dose-response relationship. Stratified analysis and effect modification analysis were also performed. Results: The age of 24 285 participants was (49.32±8.60) years, and the BMI was (24.22±6.09) kg/m2. There were 13 950 (57.44%) males and 2 066 (8.51%) diabetic patients. After adjusting for confounders, for every 10 µg/m3 increase in the average PM10 concentration in the first two years of the survey, the prevalence of diabetes increased [OR (95%CI) =1.05 (1.01-1.09)]and the FPG level elevated [ß (95%CI) = 0.061 (0.047-0.076) mmol/L]. The results of the restricted cubic spline analysis showed a nonlinear relationship between PM10 concentration and FPG level (P<0.001). Further subgroup analysis showed that female [OR (95%CI) =1.10 (1.03-1.18)], people over 50 years old [OR (95%CI) =1.06 (1.02-1.11) ], subjects with family history of diabetes [OR (95%CI) = 1.13 (1.04-1.23) ], and with hypertension [OR (95%CI) = 1.07 (1.02-1.12) ] had a stronger association between the prevalence of diabetes and PM10 exposure (all P interaction values were<0.05). The effects of PM10 on FPG were more significant in people older than 50 years[ß (95%CI) = 0.080 (0.050-0.109) mmol/L], with family history of diabetes [ß (95%CI) = 0.087 (0.036-0.137) mmol/L], and hypertension [ß (95%CI) = 0.077 (0.046-0.108) mmol/L] (all P interaction values were<0.05). Conclusions: Long-term exposure to ambient PM10 increases the diabetes prevalence and FPG. People older than 50 years old, with family history of diabetes and hypertension could be more sensitive to the effects of PM10 exposure.

Thiamine ameliorates inflammation of the ruminal epithelium of Saanen goats suffering from subacute ruminal acidosis.

This study aimed to examine the role of thiamine in the local inflammation of ruminal epithelium caused by high-concentrate diets. Eighteen mid-lactating (148 ± 3 d in milk; milk yield = 0.71 ± 0.0300 kg/d) Saanen goats (body weight = 36.5 ± 1.99 kg; body condition score = 2.73 ± 0.16, where 0 = emaciated and 5 = obese) in parity 1 or 2 were selected. The goats were randomly divided into 3 groups (n = 6/group): (1) control diet (concentrate:forage 30:70), (2) high-concentrate diet (HC; concentrate:forage 70:30), and (3) high-concentrate diet with 200 mg of thiamine/kg of dry matter intake (THC; concentrate:forage 70:30). Goats remained on experimental diets for 8 wk. On the last day of 8 wk, ruminal and blood samples were collected to determine ruminal parameters, endotoxin lipopolysaccharide, and blood inflammatory cytokines. Goats were slaughtered to collect ruminal tissue to determine gene and protein expression of toll-like receptor 4 (TLR4) signaling pathways. Thiamine supplementation increased ruminal pH (6.03 vs. 5.42) compared with the HC group. Propionate (21.08 vs. 31.61 mM), butyrate (12.08 vs. 19.39 mM), lactate (0.52 vs. 0.71 mM), and free lipopolysaccharide (42.16 vs. 55.87 × 103 endotoxin units/mL) concentrations in ruminal fluid were lower in THC goats compared with HC goats. Similar to plasma interleukin 1ß (IL-1ß) concentration (209.31 vs. 257.23 pg/mL), blood CD8+ percentage (27.57 vs. 34.07%) also decreased in response to thiamine. Compared with HC goats, THC goats had lower ruminal epithelium activity of the enzymes myeloperoxidase and matrix metalloproteinase (MMP) 2 and 9. In contrast to HC, THC had downregulated mRNA expression of nuclear factor-κB (NFKB), TLR4, IL1B, MMP2, and MMP9 in ruminal epithelium. Thiamine supplementation led to lower relative protein expression of IL-1ß, NF-κB unit p65, and phosphorylated NF-κB unit p65 in ruminal epithelium. Taken together, these results suggest that thiamine supplementation mitigates HC-induced local inflammation and ruminal epithelial disruption.

[Protective effect and mechanism of Lactobacillus rhamnosus on immune checkpoint inhibitors related colitis in mice].

Objective: Modeling the immune-related adverse events (irAE) colitis in mice, and explore the protective effect and related mechanism of Lactobacillus rhamnosus GG (LGG) on irAE colitis. Methods: C57BL/6 mice were divided into dextran sodium sulfate (DSS) group (n=3), DSS+anti-programmed death receptor 1 (PD-1) group (n=4), DSS+anti-PD-1+anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) Group (n=4), DSS+anti-PD-1+anti-CTLA-4+LGG group (n=4), all were given corresponding drugs and probiotics intervention. The severity of colitis were assessed by weight loss, disease activity index (DAI), colon length, colon histopathological score. The inflammatory cytokines and T cell immunity of CD4+, CD8+, FoxP3+regulatory T cells (Treg), were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining respectively. Results: Compared to DSS group, the Day 9 weight [(87.40±1.79)% vs (94.57±0.53)%, P<0.05], colon length [(5.33±0.27)cm vs (6.63±0.12)cm, P<0.05] were lower, and DAI score(2.66±0.24 vs 0.89±0.48), colon histopathological score (12.50±1.04 vs 5.67±0.33), tumor necrosis factor-α (TNF-α) (6.73±1.68 vs 0.91±0.40) (P<0.05), as well CD8+T cells (156.80±8.84 vs 89.00±6.66) and FoxP3+Treg cells (103.80±2.66 vs 48.33±3.18) (P<0.05) were higher in DSS+anti-PD-1+anti-CTLA-4 group. Compared to DSS+anti-PD-1+anti-CTLA-4 group, the DAI score(1.83±0.17 vs 2.66±0.24), colonic histopathology score (8.75±0.63 vs 12.50±1.04), TNF-α level (1.32±0.18 vs 6.73±1.68) (P<0.05) were lower; and CD8+T cells(97.75±3.75 vs 156.80±8.84, P<0.01) level was lower with higher FoxP3+Treg cells (126.00±8.33 vs 103.80±2.66, P=0.046) in DSS+anti-PD-1+anti-CTLA-4+LGG group. Conclusion: DSS combined with anti-PD-1 and anti-CTLA-4 can successfully modeling the irAE colitis in mice, LGG can reduce irAE colitis severity by regulating Treg cells.

[The differential diagnosis for novel coronavirus pneumonia and similar lung diseases in general hospitals].

Novel coronavirus pneumonia was a novel coronavirus infection that has dominated pulmonary infection since December 2019. The main manifestations were fever, dry cough, shortness of breath, normal or leukopenia in peripheral blood and changes in chest CT and in severe cases, multiple organ failure might occur. The National Health Commission, PRC has revised the consensus on diagnosis and treatment seven times in a short period of time, indicating the growing understanding of the disease. Patients with novel coronavirus pneumonia usually had history of travelling or living in the epidemic area including Wuhan within 14 days before onset, or have been exposed to patients who had fever or respiratory symptoms from the epidemic area, or had clustering diseases. However, novel coronavirus pneumonia was becoming more and more blurred after vanishing epidemic. The diagnosis and differential diagnosis of novel coronavirus pneumonia were challenges not only because of large number of tourists increasing dramatically after the relieving of epidemic, but also patients with other diseases from different areas to search for medical care. In this article, the clinical and chest imaging features of the novel coronavirus pneumonia were reviewed and compared with other infections and non-infectious diffuse pulmonary diseases. We try to find the similarities and differences among them, and to identify clues to the diagnosis of novel coronavirus pneumonia, so as to ensure accurate diagnosis and treatment.

Effects of arginase inhibition via jugular infusion of Nω-hydroxy-nor-l-arginine on metabolic and immune indices in lactating dairy cows.

Transformation of Arg to nitric oxide and ornithine (Arg-Orn) constitutes the main route of Arg metabolism in mammals. The primary objective of this work was to determine the effects of inhibiting the Arg-Orn pathway via Nω-hydroxy-nor-l-arginine (nor-NOHA) on health of lactating cows. Furthermore, we also explored the effect of Arg-Orn inhibition on the efficiency of nitrogen utilization to find support for previous research that showed the inhibition of Arg-Orn inhibited milk protein synthesis. Six healthy Chinese Holstein cows of similar body weight (550.0 ± 20 kg), parity (4.0 ± 0), body condition score (3.0 ± 0), milk yield (21.0 ± 1.0 kg), and days in milk (80 ± 2 d) were selected and randomly assigned to 3 treatments in a replicated 3 × 3 Latin square design with 22 d for each period (7 d for infusion and 15 d for washout). The treatments were (1) saline infusion (control); (2) infusion of 125 mg/L of nor-NOHA; and (3) infusion of 125 mg/L of nor-NOHA with 9.42 g/L of Arg. Dry matter intake, apparent digestibility of nutrients, urinary N, N in milk, and blood indices of metabolism and immune function were determined. Compared with the control, the infusion of nor-NOHA had no effect on the concentrations of cholesterol, high-density lipoproteins, IgA, IL-1ß, tumor necrosis factor-α, and alanine transaminase. In addition, the dry matter intake, apparent digestibility of N, and the concentration of milk protein N in the Nor-NOHA did not differ from the control; however, the infusion of nor-NOHA and Arg resulted in greater concentrations of high-density lipoprotein, IgA, IL-1ß, and tumor necrosis factor-α, and lower concentrations of cholesterol in serum compared with the control. Moreover, the addition of Arg to cows infused with nor-NOHA increased the concentration of nitrate (the indicator of nitric oxide) in serum and was associated with greater milk protein N production due to greater milk yield compared with those infused with nor-NOHA. Overall, the results indicated important roles of Arg in immunity and mammary N utilization, whereas a minor role of the Arg-Orn pathway in these physiologic processes was found.

Inhibition of arginase via jugular infusion of Nω-hydroxy-nor-l-arginine inhibits casein synthesis in lactating dairy cows.

A previous in vitro study revealed that Arg elicits positive effects on casein synthesis through alterations of the Arg-ornithine pathway in bovine mammary epithelial cells. The main purpose of this work was to determine the effects of arginase inhibition using Nω-hydroxy-nor-l-arginine (nor-NOHA) on milk protein synthesis in vivo. Six healthy Chinese Holstein cows with similar body weight (550.0 ± 20 kg; means ± standard deviation), parity (4), body condition score (3.0), milk yield (21.0 ± 1.0 kg), and days in milk (80 ± 2) were selected and randomly assigned to 3 treatments in a replicated 3 × 3 Latin square design with 22 d for each period (7 d for infusion and 15 d for washout). The treatments were (1) control: saline infusion; (2) nor-NOHA: infusion of 125 mg/L of nor-NOHA; (3) nor-NOHA + Arg: infusion of 125 mg/L of nor-NOHA with 9.42 g/L of Arg. The activity of enzymes related to Arg metabolism, milk protein synthesis, and expression of AA transporters was determined. The infusion of nor-NOHA decreased the activity of arginase but had no effect on the activity of ornithine decarboxylase and nitric oxide synthase in serum, and these responses were the same at the gene expression level in mammary gland. In addition, the infusion of nor-NOHA also reduced protein and fat synthesis in milk but had no effect on milk yield. When Arg was infused with nor-NOHA, the activity of total arginase, ornithine decarboxylase, and nitric oxide synthase, and the concentration of casein, protein, and fat in milk did not change compared with the nor-NOHA group, but the milk protein yield, the expression of some Arg transporters (SLC7A5 and SLC7A8), and milk yield increased. Overall, results verified previous in vitro findings indicating that synthesis of casein protein is closely regulated by the Arg-ornithine pathway in bovine mammary gland.

[Efficacy and safety of anlotinib in 16 patients with advanced non-small cell lung cancer].

Objective: To evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage ⅢB/Ⅳ NSCLC who progressed after two lines or more regimens were randomized into anlotinib group (12 mg daily from day 1 to 14 of a 21-day cycle) or placebo group with ratio of 2∶1. Study drugs or placebo were given until disease progression or intolerable toxicity. The primary endpoint was overall survival (OS), and the second endpoints were progression free survival (PFS), objective response rate, and disease control rate. Results: Between April 2015 and December 2015, twenty-four patients were assigned at Peking Union Medical College Hospital. The baseline characteristics of the anlotinib group (n=16) and placebo group (n=8) were fairly comparable. The median OS was 12.7 months in anlotinib group and 11.1 months in placebo group (P=0.460).The median PFS was 4.0 months in anlotinib group and 1.4 months in placebo group (P=0.065).The common adverse events were manageable such as hypertension, hand-foot syndrome, thyroiddy sfunction. No drug-related mortality occurred. Conclusions: Anlotinib had a trend of improvement in OS and PFS as third-line treatment or beyond in advanced NSCLC compared with placebo with manageable toxicity. ClinicalTrials:: NCT02388919.

[Paired comparative study of risk factors related to aneurysm rupture during hospitalization].

Objective: Aneurysm rupture during in-hospital period contributes to the exceedingly high morbidity and mortality of inpatients with untreated aneurysm. However, risk factors for aneurysm rupture during hospitalization were scarcely focused in previous reports. The aim of this study was to investigate the risk factors of aneurysm rupture during hospitalization and to propose clinical strategies improving prognosis. Methods: Patients with intracranial aneurysm (lA) rupture during hospitalization were identified in our prospective cohort of consecutive patients admitted to Beijing Tiantan Hospital between Jan 2014 to Dec 2017. The ruptured cases were randomly paired with control cases without rupture during hospitalization (controlling age and gender) in a proportion of 1∶2 from the cohort. An observational comparative study was conducted between the two groups. Results: Tevelve cases with IAs rupture during hospitalization were identified among 4 429 cases with IAs. Twenty-four control cases were matched for gender (male∶female=5∶7) and age distribution. A history of pre-hospital aneurysm rupture was indicated as a risk factor for IA rupture during hospitalization (OR=8.333, 95% CI 1.480-46.936, P=0.011). The irregular shape (OR=10.133, 95% CI 1.941-52.902, P=0.005)and an inflow angle<60°(OR=41.800, 95% CI 4.311-405.335, P=0.000)were morphologic factors associated with IA rupture of inpatients. Conclusions: A history of pre-hospital IA rupture, IAs with irregular shape and an inflow angle <60° were risk factors associated with IAs rupture of inpatients. Unfavorable outcomes were observed in cases with IA rupture during hospitalization. A one-stage hybrid surgical strategy combining diagnosis, evaluation and intervention could reduce the length of preoperative stay, as well as the rupture risk of inpatients with IAs.

Short communication: Arginase inhibition reduces the synthesis of casein in bovine mammary epithelial cells.

The main purpose of this work was to determine the effect of arginase inhibition via Nω-hydroxy-nor-l-arginine (nor-NOHA) on casein synthesis in bovine mammary epithelial cells (BMEC). Passage 2 BMEC isolated from dairy cows were seeded to 6-well plates and randomly divided into 4 treatments: (1) control [Dulbecco's modified Eagle medium:Nutrient Mixture F-12 medium (DMEM/F12)]; (2) nor-NOHA (DMEM/F12 + 1 mmol/L nor-NOHA); (3) nor-NOHA + arginine (DMEM/F12 + 1 mmol/L nor-NOHA + 3.2 mmol/L Arg); and (4) nor-NOHA + ornithine (DMEM/F12+ 1 mmol/L nor-NOHA + 1 mmol/L Orn). Then, we determined the activity of enzymes related to Arg metabolism and casein synthesis in BMEC and the proliferation of cells. The addition of nor-NOHA reduced the activity of arginase and ornithine decarboxylase but had no effect on the activity of nitric oxide synthase, and these responses were the same at the gene expression level. In addition, supplementation of nor-NOHA in BMEC reduced cellular proliferation and casein synthesis. Addition of Arg to nor-NOHA resulted in cellular proliferation and casein synthesis similar to that of nor-NOHA alone. In contrast, addition of Orn to the medium with nor-NOHA increased the synthesis of casein and cellular proliferation compared with Nor-NOHA. In conclusion, suppression of the Arg-arginase-Orn pathway reduced casein synthesis and cellular proliferation, which indicated that this pathway is an important regulator of the synthesis of casein in BMEC.

Effects of dietary physically effective neutral detergent fiber content on the feeding behavior, digestibility, and growth of 8- to 10-month-old Holstein replacement heifers.

The objective of this study was to evaluate the effects of dietary physically effective neutral detergent fiber (peNDF) content on the feeding behavior, digestion, ruminal fermentation parameters, and growth of 8- to 10-mo-old dairy heifers and to predict the adequacy of dietary fiber in growing dairy heifers. Twenty-four Holstein dairy heifers (245 ± 10.8 d of age, 305.6 ± 8.5 kg initial live weight) were randomly divided into 4 treatments with 6 replicates as a completely randomized design. During the 60-d period with a 10-d adaptation, heifers were offered 1 of 4 diets, which were chemically identical but included different peNDF8.0 (particle size is >8 mm and <19 mm) content (% DM): 10.8, 13.5, 18.0, or 19.8%, which was achieved by chopping forage into different lengths (fine = 1 cm, short = 3 cm, medium = 5 cm, and long = 7 cm). The concentrate and silage were mixed and fed restrictedly and exclusive of forage (Chinese ryegrass hay) were offered ad libitum. The body weight and frame size of the heifers were measured every 15 d during the experimental period. Samples of the rumen content (2 h after the morning feeding) were taken for pH, ammonia, and volatile fatty acid determination. The dry matter intake and average daily gain of the heifers were not significantly affected by peNDF8.0 content. The body frame size (including withers height, body length, and heart girth) of the heifers was not increased significantly by enhanced peNDF8.0 content. Ruminal pH and ammonia concentration were both increased with increasing dietary peNDF8.0 content. The ruminal total volatile fatty acid concentration and percentage of acetate and butyrate profiles were not significantly affected by dietary peNDF8.0 content. However, the enhanced peNDF8.0 content led to a decrease in the propionate percentage. The ratio of acetate to propionate in the 13.5% treatment was highest among the treatments. Increasing the particle size and dietary peNDF8.0 content resulted in increased eating and chewing time but had no effect on rumination time. Heifer total eating and chewing time and eating and chewing time per kilogram of dry matter intake were increased with increasing dietary peNDF8.0 content. The apparent digestibility of acid detergent fiber and crude protein was improved with an increasing content of dietary peNDF8.0. The results suggest that an optimal or advisable dietary particle size and peNDF8.0 content improves chewing activity, rumen fluid pH, and ruminal fermentation. The data based on feeding behavioral and growth responses of heifers as well as rumen fermentation and digestion by improving total eating and chewing time indicate that 18.0% dietary peNDF8.0 content is the most suitable for 8- to 10-mo-old Holstein heifers.