Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses.

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.

Author Correction: Mapping the world's free-flowing rivers.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mapping the world's free-flowing rivers.

Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.

DeepHost: phage host prediction with convolutional neural network.

Next-generation sequencing expands the known phage genomes rapidly. Unlike culture-based methods, the hosts of phages discovered from next-generation sequencing data remain uncharacterized. The high diversity of the phage genomes makes the host assignment task challenging. To solve the issue, we proposed a phage host prediction tool-DeepHost. To encode the phage genomes into matrices, we design a genome encoding method that applied various spaced $k$-mer pairs to tolerate sequence variations, including insertion, deletions, and mutations. DeepHost applies a convolutional neural network to predict host taxonomies. DeepHost achieves the prediction accuracy of 96.05% at the genus level (72 taxonomies) and 90.78% at the species level (118 taxonomies), which outperforms the existing phage host prediction tools by 10.16-30.48% and achieves comparable results to BLAST. For the genomes without hits in BLAST, DeepHost obtains the accuracy of 38.00% at the genus level and 26.47% at the species level, making it suitable for genomes of less homologous sequences with the existing datasets. DeepHost is alignment-free, and it is faster than BLAST, especially for large datasets. DeepHost is available at https://github.com/deepomicslab/DeepHost.

Natural disasters: a comprehensive study using EMDAT database 1995-2022.

INTRODUCTION: The frequency, intensity, and geographical reach of natural disasters, fueled in part by factors such as climate change, population growth, and urbanization, have undeniably been escalating concerns around the world. DESIGN AND METHODS: This is a retrospective analysis of natural disasters recorded in the Emergency Events Database from 1995 to 2022. RESULTS: Between 1995 and 2022, 11,360 natural disasters occurred, with a mean of 398 per year. Asia experienced the most disasters (4390) and the highest number of casualties (918,198). Hydrological disasters were the most common subgroup (4969), while geophysical disasters led in terms of deaths (770,644). Biological disasters caused the most injuries (2544), particularly in Africa. CONCLUSION: Recognizing the historical impacts of the various subtypes of natural disasters may help different regions better risk analyze and mitigate the unique risks associated with such events.

[Effect of changes in posterior tibial slope on the mid-term clinical outcomes of Oxford unicompartmental knee arthroplasty].

Objective: To investigate the impact of changes in the posterior tibial slope (PTS) in Oxford unicompartmental knee arthroplasty (OUKA) on the mid-term clinical outcomes of postoperative patients. Methods: This study was a follow-up study. The data of 135 patients (150 knees) who underwent OUKA at the China-Japan Friendship Hospital from January 2012 to January 2013 were analyzed retrospectively. The patients were followed-up for at least ten years. According to the changes in PTS of the medial tibial plateau before and after surgery, patients were divided into three groups: group A (PTS decreased by more than 5°), group B (PTS changed by 5° or less), and group C (PTS increased by more than 5°). The Knee Society Clinical Score (KSS-C), Knee Society Functional Score (KSS-F), Oxford Knee Score (OKS), Forgotten Joint Score (FJS), and knee range of motion (ROM) among the three groups were compared at the last follow-up. Results: Prior to the final follow-up assessment, six patients expired, and an additional nine patients were lost to follow-up. A total of 120 patients (135 knees) were enrolled in this study (30 males and 90 females). The mean age was (66.29±8.62) years, and the follow-up time was (10.54±0.72) years. Group A consisted of 32 patients (34 knees), group B comprised 77 patients (90 knees), and group C included 11 patients (11 knees). One knee in group A suffered prosthesis loosening, and two knees in group C experienced postoperative bearing dislocation, one knee encountered bearing fragmentation. The incidence of postoperative complications differed significantly among the three groups (P<0.05). The preoperative OKS was (33.91±6.59) points, KSS-F was (43.46±8.99) points, KSS-C was (41.05±5.70) points and ROM was 115.23°±13.53°; after the surgery, they changed to (18.82±7.01) points, (81.51±7.34) points, (82.64±7.94) points, and 119.07°±8.62°, respectively, and all the differences were statistically significant (all P<0.001). In terms of postoperative outcomes, group A had an OKS of (21.44±8.46) points and a FJS of (63.83±11.40) points, group B had an OKS of (17.07±5.81) points and a FJS of (70.49±12.45) points, group C had an OKS of (25.09±5.07) points and a FJS score of (59.48±10.09) points; the differences among the three groups were all statistically significant (all P<0.05), but there were no significant differences in the postoperative KSS scores and ROM among the three groups (all P>0.05). Conclusions: After OUKA, better mid-term clinical outcomes are achieved when ΔPTS is<5°. Although the recommended central value for PTS in OUKA is 7° according to Oxford, it should be individualized, and it is recommended to consider the preoperative angle, with a change of less than 5° before and after surgery.

[Long-term prophylactic therapy combined with on-demand therapy for the control of hereditary angioedema--Comment on the 2021 edition of the international WAO/EAACI guideline for the management of hereditary angioedema].

The 2021 edition of the international World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) guideline for the management of hereditary angioedema (HAE) is mainly based on high-quality randomized controlled trials. It provides clinical classification for HAE and offers graded recommendations for on-demand therapy, short-term prophylactic therapy, and long-term prophylactic therapy. Additionally, it provides management strategies for people with different HAE types. This article focused on the interpretation of short-term, long-term prophylactic therapy and on-demand therapy for HAE, supplemented with the latest clinical evidence, aiming to provide references for the long-term management of HAE.

[Pituitary Crooke cell neuroendocrine tumor of adrenocorticotropic hormone differentiation-specific transcription factor lineage: a clinicopathological analysis of six cases].

Objective: To investigate the clinicopathological features of Crooke cell tumor of adrenocorticotropic hormone differentiation specific transcription factor (TPIT, also known as transcription factor 19, TBX19) lineage neuroendocrine tumors. Methods: Six cases of Crooke cell tumor diagnosed at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China from October 2019 to October 2023 were collected. The clinical and pathological features of these cases were analyzed. Results: Among the six cases, one was male and five were female, with ages ranging from 26 to 75 years, and an average age of 44 years. All tumors occurred within the sella turcica. Clinical presentations included visual impairment in two cases, menstrual disorders in one case, Cushing's syndrome in one case, headache in one case, and one asymptomatic case discovered during a physical examination. Preoperative serum analyses revealed elevated levels of cortisol and adrenocorticotropic hormones in two cases, elevated cortisol in two cases, elevated adrenocorticotropic hormone in one case, and one case with a mild increase in prolactin due to the pituitary stalk effect. Magnetic resonance imaging revealed uneven enhancement of masses with maximum diameters ranging from 1.7 to 3.2 cm, all identified as macroadenomas. Microscopically, tumor cells exhibited irregular polygonal shapes, solid sheets, or pseudo-papillary arrangements around blood vessels. The cell nuclei were eccentric or centrally located, varying in size, with abundant cytoplasm. Some tumor cells showed perinuclear halo. Immunohistochemistry demonstrated diffuse strong positivity for TPIT in five cases, focal weak positivity for TPIT in one case, diffuse strong positivity for adrenocorticotropic hormone in all cases, and faint staining around the nuclei in a few cells. CK8/18 showed a strong positive ring pattern in more than 50% of tumor cells, focal weak positive expression of p53, and the Ki-67 positive index ranged 1%-5%. Periodic acid-Schiff staining revealed positive cytoplasm and negative perinuclear areas. Conclusions: Crooke cell tumor is a rare type of pituitary neuroendocrine tumors. Its pathological characteristics include a distinctive perinuclear clear zone and immunohistochemical markers, such as CK8/18 exhibiting a ring or halo pattern. This entity represents a high-risk subtype among pituitary neuroendocrine tumors, displaying a high risk of invasion and a propensity for recurrence. Accurate diagnosis is crucial for the postoperative follow-up and multimodal treatment planning.

Properties of Cosmic-Ray Sulfur and Determination of the Composition of Primary Cosmic-Ray Carbon, Neon, Magnesium, and Sulfur: Ten-Year Results from the Alpha Magnetic Spectrometer.

We report the properties of primary cosmic-ray sulfur (S) in the rigidity range 2.15 GV to 3.0 TV based on 0.38×10^{6} sulfur nuclei collected by the Alpha Magnetic Spectrometer experiment (AMS). We observed that above 90 GV the rigidity dependence of the S flux is identical to the rigidity dependence of Ne-Mg-Si fluxes, which is different from the rigidity dependence of the He-C-O-Fe fluxes. We found that, similar to N, Na, and Al cosmic rays, over the entire rigidity range, the traditional primary cosmic rays S, Ne, Mg, and C all have sizeable secondary components, and the S, Ne, and Mg fluxes are well described by the weighted sum of the primary silicon flux and the secondary fluorine flux, and the C flux is well described by the weighted sum of the primary oxygen flux and the secondary boron flux. The primary and secondary contributions of the traditional primary cosmic-ray fluxes of C, Ne, Mg, and S (even Z elements) are distinctly different from the primary and secondary contributions of the N, Na, and Al (odd Z elements) fluxes. The abundance ratio at the source for S/Si is 0.167±0.006, for Ne/Si is 0.833±0.025, for Mg/Si is 0.994±0.029, and for C/O is 0.836±0.025. These values are determined independent of cosmic-ray propagation.

Temporal Structures in Positron Spectra and Charge-Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.

Temporal Structures in Electron Spectra and Charge Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic electron fluxes in the rigidity interval from 1.00 to 41.9 GV based on 2.0×10^{8} electrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The electron fluxes exhibit variations on multiple timescales. Recurrent electron flux variations with periods of 27 days, 13.5 days, and 9 days are observed. We find that the electron fluxes show distinctly different time variations from the proton fluxes. Remarkably, a hysteresis between the electron flux and the proton flux is observed with a significance of greater than 6σ at rigidities below 8.5 GV. Furthermore, significant structures in the electron-proton hysteresis are observed corresponding to sharp structures in both fluxes. This continuous daily electron data provide unique input to the understanding of the charge sign dependence of cosmic rays over an 11-year solar cycle.

Gadoxetic acid in hepatocellular carcinoma and liver metastases: pearls and pitfalls.

Gadoxetic disodium (Primovist) is a hepatocyte-specific magnetic resonance imaging (MRI) contrast agent with increasing popularity with its unique dual dynamic and excretory properties in focal liver lesion detection and characterisation. In-depth knowledge of its diagnostic utility and pitfalls in hepatocellular carcinoma (HCC) and liver metastases is crucial in facilitating clinical management. The current article reviews the pearls and pitfalls in these aspects with highlights from the latest research evidence. Pearls for common usage of Primovist in HCC includes detection of precursor cancer lesions in cirrhotic patients. Hepatobiliary phase hypointensity precedes arterial phase hyperenhancement (APHE) in hepatocarcinogenesis. Hepatobiliary phase hypointense nodules without APHE can represent early or progressed hepatocellular carcinoma (HCC) and high-grade dysplastic nodules. In addition, Primovist is useful to differentiate HCC from pseudolesions. Pitfalls in diagnosing HCC include transient tachypnoea in the arterial phase, rare hepatobiliary phase hyperintense HCC, and decompensated liver cirrhosis compromising image quality. Primovist is currently the most sensitive technique in diagnosing liver metastases before curative hepatic resection. Other patterns of enhancement of liver metastases, "disappearing" liver metastases are important pitfalls. Radiologists should be aware of the diagnostic utility, limitations, and potential pitfalls for the common usage of hepatobiliary specific contrast agent in liver MRI.

Low-noise φ-OTDR employing nonlinear optical preamplification for distributed acoustic sensing.

A phase sensitive optical time domain reflectometry sensing scheme employing a two-stage nonlinear optical preamplification system is proposed to reduce the blind spot effect in Rayleigh scattering by improving the optical power distribution and to enhance the resolution at locations of low-backscatter intensity measurements, providing a higher signal-to-noise ratio for distributed acoustic measurements; the developed system has been tested in-laboratory and on in-field monitoring of a survey well in Cottessen, The Netherlands. The characterization shows strain noise levels below 1 nɛ for a 10 kHz sampling rate.

Clashes and crowds: protests, riots, and other mass gathering events in North America 2021-2022.

OBJECTIVE: This study aimed to provide an overview of the scope and challenges of historic events and help better prepare emergency healthcare services for future similar mass gathering events. STUDY DESIGN: This was a retrospective descriptive analysis of protest and conflict events in North America from 2021 to 2022. INTRODUCTION: Recent protests, riots, and other conflict events in North America have highlighted the increasing challenges hospital-based and prehospital healthcare providers face. This study provides a retrospective descriptive analysis of protest and conflict events in North America from 2021 to 2022, which may aid emergency healthcare services in understanding the scope and challenges of historic events and help better prepare for future similar mass gathering events. METHODS: Data collection was performed using a retrospective database search through the Armed Conflict Location & Event Data Project (ACLED) database. The ACLED database was searched using the internal database search functions for recorded events that occurred in North America from January 1, 2021 to December 31, 2022. Date, event type, event subtype, the country of incident, and fatality numbers were extracted. The results were exported into an Excel spreadsheet and analyzed independently by L.C., H.S., and R.H. RESULTS: There were a total of 52,529 recorded events of political conflict in North America, with 30,269 events in 2021 and 29,260 in 2022. Political conflict events included protests (40,934, 68.8%), violence against civilians (11,532, 19.4%), strategic developments (2,819, 4.7%), battles (2,293, 3.9%), riots (1,909, 3.2%), and remote violence (42, 0.1%). Violence against civilians caused the highest fatalities (13,466, 82.6%), followed by battles (2,662, 16.3%), riots (111, 0.7%), strategic developments, remote violence, and protests (57, 6, and 3 respectively). CONCLUSION: Mexico and the United States accounted for most of the political conflicts in North America across 2021 and 2022. In Mexico, protests and violence against civilians were the most common types of conflict, with the latter accounting for the comparatively high fatality compared with the other countries. Battles in Mexico between cartels were the most deadly political conflicts recorded in North America.

[Pregnancy outcome analysis after radiofrequency ablation of monochorionic twin pregnancy in different gestational weeks and psychological intervention].

Objective: To investigate the effect of different gestational weeks and psychological intervention on pregnancy outcome in patients with monochorionic twin pregnancy. Methods: The clinical data of 68 patients with monochorionic twin pregnancy in the middle and late pregnancy who were treated with radiofrequency ablation in the First Affiliated Hospital of Zhengzhou University from March 2017 to April 2021 were retrospectively analyzed, including 54 patients with single chorionic and single amniotic sac and 14 patients with single chorionic and double amniotic sac. Patients were divided into three groups according to the gestational weeks:<20 weeks (n=36), 20-23 weeks (n=17) and ≥24 weeks (n=15); and were divided into intervention group (n=40) and control group (n=28) according to the preoperative psychological intervention. The pregnancy outcome of patients with different pregnancy reduction and the effect of psychological intervention on pregnancy outcome was analyzed. Results: The age of 68 patients was (30.2±4.6) years old, the gestational age was (22.2±3.2) weeks, and 60 cases (88.2%) were live births after fetal reduction. There were no significant difference in age [(31.8±4.7),(28.3±5.0),(30.3±4.0) years old] (P=0.098), abortion rate, preterm birth rate, live birth rate, delivery mode, gestational week of preterm birth, gestational week of delivery, and neonatal weight between the two groups at different gestational weeks (all P>0.05). The ages of the intervention group and the control group were (30.6±4.7) and (29.4±4.0) years old (P=0.352). After psychological intervention for 40 patients in the intervention group, the anxiety score after pregnancy reduction was reduced from (54.8±6.8) to (37.3±7.3) (P<0.001), while the depression score decreased from (62.7±7.2) to (33.2±2.4) (P<0.001). Compared with patients in the control group (12.5%, n=5), the proportion of postoperative discomfort in the intervention group was higher (53.6%, n=15) (P<0.001). Compared with the control group, there were no statistically significant difference in the postoperative preterm birth rate, abortion rate, live birth rate, delivery mode, gestational week of preterm birth, gestational week of delivery, and neonatal weight in the intervention group (all P>0.05). Conclusions: Radiofrequency ablation is a safe and effective minimally invasive technique. For complex monochorionic twin pregnancies, early fetal reduction (<20 weeks) and preoperative psychological intervention can provide a solid guarantee for a good postoperative pregnancy outcome.

[Correlation between fluid parameter and cardiovascular events in hemodialysis patients based on repeated body composition analyses].

Objective: To explore the correlation between fluid load index and cardiovascular events in hemodialysis patients based on repeated body composition analyses. Methods: A prospective cohort study was conducted to collect the clinical data of patients undergoing maintenance hemodialysis (MHD) in the Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine from July to September 2020. The pre-dialysis fluid overload (FO) index-overhydration (OH) was measured by bioelectrical impedance method, and the follow-up monitoring was conducted every 6 months. According to the baseline OH value, patients were divided into non-FO group (OH≤2.5 L) and FO group (OH>2.5 L). Moreover, according to the repeated measurements, the patients were divided into continuous non-FO group, continuous FO group and intermittent FO group. All patients were followed up until October 1, 2022, and the outcomes were recorded. The end point of follow-up was cardiovascular events. The cumulative incidence of cardiovascular events was calculated by the Kaplan-Meier method, and the risk factors of cardiovascular events were analyzed by Cox proportional hazards regression model. Results: A total of 289 patients were included, including 88 patients (30.4%) with FO and 201 patients (69.6%) with non-FO. There were 168 males (58.1%) and 121 (41.9%) females, with an average age of (58±13) years and an average follow-up time of (22.0±6.5) months. Kaplan-Meier analysis showed that the incidence of cardiovascular events in the baseline FO group was higher than that in the non-FO group (log-rank χ2=14.44, P<0.001). The incidence of cardiovascular events in both the continuous FO group and the intermittent FO group was higher than that in the continuous non-FO group (log-rank χ2=41.47, P<0.001; log-rank χ2=18.36, P<0.001). After adjustment for gender, age, comorbidities, and biochemical indicators, the incidence of cardiovascular events in the baseline FO group was 1.850 times of the non-FO group (95%CI: 1.046-3.271, P=0.034). The incidence of cardiovascular events in the continuous FO group was 4.679 times of the continuous non-FO group (95%CI: 2.189-10.002, P<0.001). The incidence of cardiovascular events in the intermittent FO group was 3.410 times of the continuous non-FO group (95%CI: 1.696-6.857, P=0.001). Conclusions: OH value measured by bioelectrical impedance can be used as an important reference index for clinical monitoring of cardiovascular events in MHD patients. Continuous chronic and intermittent exposures to FO are risk factors for cardiovascular events in hemodialysis patients.

[Clinical results of medial mobile bearing unicompartmental knee arthroplasty using kinematic alignment technique with at least 5-years follow-up].

Objective: To evaluate the mid-term results of kinematic alignment technique in Oxford mobile bearing unicompartmental knee arthroplasty (OUKA). Methods: The clinical data of first 98 knees OUKA performed from June 2015 to January 2017 using kinematic alignment technique with at least 5-year follow-up were retrospectively analyzed, including 28 knees in 24 males and 70 knees in 62 females. The mean surgical age was (68.4±8.0) years. The clinical data of patients before operation and at the last follow-up were recorded and compared. The knee Hospital for Special Surgery (HSS) score, visual analogue scale (VAS) of pain, range of motion, surgical complications and radiological assessment were analyzed to evaluate the efficacy of kinematic alignment technique in OUKA. Results: The mean follow-up was (70.9±5.9) months (60-81 months). The mean operation time was (56.4±9.1) minutes. There was no conversion to total knee replacement, no collateral ligament injury and no fracture in operation. The postoperative hospital stay was (5.8±1.9) days. Postoperative hemoglobin drop was (12.7±5.5) g/L. There was no blood transfusion. No patient died during perioperative period. No serious adverse events related to surgery occurred after operation, such as pulmonary embolism, fat embolism, cardio-cerebrovascular accident, etc. No revision, bearing dislocation, periprosthetic joint infection, prosthesis aseptic loosening, contralateral compartment arthritis progression occurred at final follow-up. Three patients reported persistent unexplained knee pain. Afther the operation, the HSS score increased from 59.1±8.2 to 91.8±5.6 after the operation, the range of motion increased from 122.4°±10.0° to 125.6°±7.1°, and the VAS score decreased from 6.9±0.8 to 1.6±1.2 (all P<0.05). Radiological assessment showed that 92.9%(91/98) implant positions were ideal and 7 knees were outliers. The mean HKAA was 173.3°±3.7° before surgery and it was 177.2°±3.0° after surgery (P=0.038). The mean A angle of femur varus/valgus angle was 2.0°±2.8° (-11°-13°), and the mean B angle of femur flexion/extension angle was 4.8°±3.4°(0°-17°). The mean tibia valgus/valgus angle E angle was 1.0°±1.9°(-4°-9°), and the mean F angle was 6.7°±2.3°(1°-12°). The mean postoperative prosthesis distance was (4.29±2.46)mm(2-7 mm). Conclusions: It's demonstrated that the kinematic alignment technique follows the design principle of OUKA, has satisfactory mid-term results. The radiological assessment of the prosthesis is acceptable.

[Clinical characteristics analysis of patients with severe immune checkpoint inhibitors related myocarditis].

Objective: To analyze the clinical characteristics of patients with severe immune checkpoint inhibitors (ICIs) related myocarditis. Methods: A retrospective study was conducted on the 50 patients with ICIs-related myocarditis in the multidisciplinary cardio-oncology clinic of Zhongshan Hospital affiliated to Fudan University from April 2020 to April 2022. The age of patients was (63.7±10.8) years old, including 37 males and 13 females. The patients were divided into the mild group (n=37) and the severe group (n=13) according to severity. The differences of basic characteristics, clinical manifestations, laboratory tests, auxiliary examination, combined irAEs, treatment and outcomes between the two groups of patients were analyzed. Results: The immunotherapy time [M(Q1,Q3)] of patients in the mild group and severe group were 81 (49, 134) and 24 (20, 116) days, respectively (P<0.05). In the severe group, the levels of cTnT [0.605 (0.317, 1.072) µg/L], NT-proBNP [1 126 (386, 1 744) ng/L], CK-MB [78 (48, 238) U/L], and CK-MM [240 (45, 6 543) U/L] were higher than those in the mild group [0.104 (0.045, 0.189) µg/L, 237 (39, 785) ng/L, 24 (20, 33) U/L, 108 (72, 168) U/L, respectively] (all P<0.05). The left ventricular ejection fraction of the severe group [64% (57%, 65%)] was lower than that of the mild group [66% (63%, 69%)] (P<0.05), and the incidence of conduction block (n=4, 4/13) and abnormal ventricular wall motion (n=4, 4/13), the incidence of ICIs-related myositis (n=10, 10/13), ICIs-related hepatitis (n=4, 4/13) and ICIs-related neurotoxicity (n=4, 4/13) were higher than those in the mild group (n=1, 2.7%; n=2, 5.4%; n=16, 43.2%; n=2, 5.4%; n=1, 2.7%, respectively) (all P<0.05). The proportion of patients receiving intensified immunosuppressive therapy and mortality rate in the severe group were 12/13 (n=12) and 4/13 (n=4), which were both higher than those in the mild group [10.8% (n=4) and 0] (both P<0.05). Conclusions: The incidence of ICIs-related myocarditis is not high, but the severe rate and mortality are high. The differential diagnosis of severe ICIs related myocarditis should be combined with myocardial markers, electrocardiogram and echocardiogram, and early diagnosis and treatment can improve the prognosis of patients.

[Investigate the role of neutrophil extracellular traps in immune checkpoint inhibitor-associated myocarditis with programmed death protein-1 inhibitors involvement].

Objective: To investigate the role of neutrophil extracellular traps (NETs) in immune checkpoint inhibitor-associated myocarditis (ICIAM) with programmed death protein-1 (PD-1) inhibitors involvement, and to explore the therapeutic potential of targeting NETs in the treatment of ICIAM. Methods: Thirty 6-week-old male BALB/c mice were randomly divided into control group (n=10), myocarditis group (n=10), and treatment group (n=10). Apart from the control group, each mouse was subcutaneously injected with 100 µl of complete Freund's adjuvant containing 250 µg of mouse cardiac troponin I peptide on the 1st and 7th day. Starting on the 8th day, PD-1 inhibitor (15 µg/per mouse) was intraperitoneally injected every other day for a total of 5 times. Since 1 day before the beginning of PD-1+TnI injection, the treatment group was injected with PF-1355 (50 mg·kg-1·d-1) for 16 consecutive days. The mice's general state was observed during the whole process. Real-time fluorescence quantitative PCR (RTFQ-PCR) was carried out to evaluate the transcriptional regulation of neutrophil related chemokines, NETs, pyronecrosis related factors and proinflammatory cytokines. Immunohistochemistry, immunofluorescence and western blot were applied to determine the changes of pyrosis related molecules. Echocardiography showed the differences of main cardiac indexes while cardiac pathology compared the degree of inflammatory infiltration in 3 gruops. Results: The immunofluorescence intensity of myocardial NETs in the myocarditis group was significantly increased compared to the control group mice (2.49±0.08 and 0.99±0.26, P<0.001). The protein expression levels of pyroptosis-related NLRP3, cleaved-Caspase 1, Caspase 1, cleaved-GSDMD, GSDMD, IL-1ß and IL-18 in myocardial tissue of the model group were higher than those of the control group (all P<0.05). After treatment with PF-1355, compared to the myocarditis group, the left ventricular ejection fraction (LVEF) (73.58%±5.31% and 58.12%±3.19%, P<0.001) and left ventricular fraction shortening (LVFS) (39.78%±4.31% and 33.89%±2.19%, P<0.001) increased. H-E staining showed a reduction in inflammatory infiltration area in the treatment group compared to the myocarditis group (30.12%±3.57% and 14.92%±2.46%, P<0.001). The immunofluorescence intensity of NETs decreased in the treatment group compared to the myocarditis group (2.52±0.04 and 1.03±0.05, P<0.001). The levels of NLRP3 and other pyroptosis-related molecules were downregulated in the treatment group compared to the myocarditis group (all P<0.05). Conclusions: NETs lead to myocardial cell pyroptosis by activating the NLRP3 inflammasome in PD-1 inhibitor-associated myocarditis. The specific MPO inhibitor PF-1355 shows a therapeutic potential by regulating the formation of NETs, decreasing NLRP3 level and relieving myocardial pyroptosis, thus reducing myocardial damage.

[Clinical features and related factors of invasive pulmonary aspergillosis in patients with acute exacerbation of chronic obstructive pulmonary disease].

Objective: To study the clinical features and related factors of invasive pulmonary aspergillosis (IPA) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: This retrospective study enrolled patients hospitalized for AECOPD in ten tertiary hospitals of China from September 2017 to July 2021. AECOPD patients with IPA were included as case group, AECOPD patients without IPA were randomly selected as control group from the same hospitals and same hospitalization period as the patients with IPA using the random function in the software of Microsoft Excel 2003, at a ratio of 2∶1. The clinical characteristics, treatment and outcome were compared between the two groups. Binary logistic regression model was used to analyze the factors associated with IPA in AECOPD patients. Results: A total of 14 007 inpatients with AECOPD were included in this study, and 300 patients were confirmed to have IPA, with an incidence rate of 2.14%. According to the above matching method, 600 AECOPD patients without aspergillus infection were enrolled as the control group. The age of the case group and the control group were (72.5±9.7) and (73.5±10.3) years old, with 78.0%(n=234) male and 76.8%(n=461) male, respectively. There were no significant differences in age and gender composition between the two groups (all P>0.05). The prognosis of case group was significantly worse than that of the control group, with longer hospital stay [M(Q1,Q3)], [14 (10-20) d vs 11 (8-15) d, P<0.001], higher ICU admission rate [16.3% (49 case) vs 10.0% (60 case), P=0.006], higher in-hospital mortality [4.0% (12 cases) vs 1.3% (8 cases), P=0.011], and higher hospitalization costs (28 000 ¥ vs 13 700 ¥, P<0.001). The smoking index of the case group and proportions of patients with diabetes mellitus, chronic pulmonary heart disease in the case group were significantly higher than those in control group (all P<0.05). In terms of clinical features, the proportions of patients with cough, expectoration, purulent sputum, hemoptysis and fever in the case group were higher than those in the control group, the serum albumin was significantly lower than that in the control group, and the proportions of patients with bronchiectasis and pulmonary bullae on imaging were significantly higher than those in the control group (all P<0.05). Diabetes (OR=1.559, 95%CI: 1.084-2.243), chronic pulmonary heart disease (OR=1.476, 95%CI: 1.075-2.028), bronchiectasis (OR=1.506, 95%CI: 1.092-2.078), pulmonary bullae (OR=1.988, 95%CI: 1.475-2.678) and serum albumin<35 g/L (OR=1.786, 95%CI: 1.325-2.406) were the related factors of IPA in patients with AECOPD. Conclusions: The incidence of IPA in AECOPD patients is relatively high and the prognosis of these patients is worse. Diabetes, chronic pulmonary heart disease, bronchiectasis, pulmonary bulla, hypoproteinemia are the related factors of IPA in patients with AECOPD.