New progress of central nervous system infectious diseases in 2021, one article inventory

*For medical professionals to read and refer to the characteristics, diagnosis and treatment of CNS infection, listen to what the experts say? Central nervous system (CNS) infection is a common and difficult critical illness
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Globally, there are more than 30 million patients with meningitis every year, and the morbidity and mortality of meningitis are relatively high
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The lack of clear diagnosis and standardized treatment is the leading cause of death, and there is an urgent need for precision medicine
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In 2021, some progress has been made in the diagnosis and treatment of CNS infectious diseases
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To this end, we invite Professor Peng Fuhua from the Department of Neurology and Neuroinfection Subspecialty of the Third Affiliated Hospital of Sun Yat-sen University to bring you an interpretation and summary of the new progress in the field of CNS infectious diseases in 2021 (video playback at the end of the article)
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3 Questions First of all, Professor Peng Fuhua raised several questions to everyone: Question 1: Why is the pathogen of respiratory/digestive/urinary tract infection the same as that of CNS infection, and the prognosis is so different? (Different sites of infection) Question 2: After the pathogen of CNS infection has been removed, why did the symptoms and signs not improve? (Different pathogenic mechanisms?) Question 3: Are the treatment ideas for respiratory/digestive/urinary tract infections the same as those for CNS infections? (Different ) As we mentioned earlier, failure to obtain a clear diagnosis and standardized treatment is the main cause of death, and precision medicine is the fundamental solution.
Where does the word "precision" come from? Precise diagnosis + precise treatment is more intuitive
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Accurate diagnosis of CNS infection: traditional main means of pathogenic microorganism detection + new diagnostic technology + artificial intelligence technology,
etc.

Precise treatment of CNS infection: On the basis of a full understanding of the pathogenesis, an individualized treatment plan that combines various pathogenic infections, post-infection and complication classification and staging is the key to reducing the fatality and disability rate
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CNS infection and immunity (1) New coronavirus and immunity Studies have found that the recent epidemic of new coronary pneumonia can cause CNS infection, but it is uncertain whether it is directly caused by CNS infection or caused by immunity.
If it directly invades the CNS, then It may be lacking attention at present
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(2) Herpes simplex virus encephalitis and autoimmune encephalitis Autoimmune encephalitis caused by herpes simplex virus encephalitis has attracted more and more attention, and its pathogenesis may be related to the release of antigens from neurons after herpes simplex virus infection of neurons cause an immune response
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The clinical manifestations of this secondary autoimmune encephalitis are diverse, and it is easy to be confused with recurrent herpes simplex encephalitis in the early stage.
Delayed treatment leads to severe neurological deficits and poor prognosis
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In addition, for herpes simplex encephalitis and autoimmune encephalitis, as early as 2018, Lancet Neurology published a large prospective study, the results showed that more than 1/4 (about 27%) of herpes simplex encephalitis patients Autoimmune encephalitis can occur, and timely diagnosis and treatment are very important
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This condition is also called bimodal encephalitis (Figure 1)
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(3) Professor Fuhua Peng introduced that cryptococcal infection-related encephalitis syndrome has encountered more than 60 cases of non-HIV cryptococcal meningitis patients in his hospital, usually 2-3 times the lumbar puncture review was negative for Cryptococcus, and suddenly new cases appeared.
A large lesion in the brain develops, and new neurological symptoms and signs appear
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This is likely to be post-infection inflammatory response syndrome (PIIRS), which can be seen during the treatment of patients with non-HIV-related cryptococcal meningitis.
Immune reconstitution inflammatory syndrome (IRIS) can also be a systemic disease, if not paid attention to , can be fatal
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Available data show that as many as 20%-30% of patients who die from cryptococcal meningitis complications die from concurrent IRIS
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Prompt us, after the induction phase, patients with cryptococcal meningitis suddenly deteriorated without obvious incentives, imaging showed multiple intracranial lesions, cerebrospinal fluid microbiological examination did not reveal Cryptococcus, PIIRS should be considered
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(4) Tuberculous meningitis It has been reported in the past that anti-N-methyl-D-aspartate receptor encephalitis is secondary to tuberculous meningitis
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(5) Others, such as inflammatory demyelinating disease of the spinal cord caused by recurrent brucellosis, and acute disseminated encephalomyelitis caused by Mycoplasma pneumoniae infection
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All in all, the concept of bimodal encephalitis is becoming more and more clear, and special attention should be paid in the process of diagnosis and treatment
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In addition to the separation of the two peaks, there are also cases where the two peaks overlap.
For example, the first peak is not treated in time or the treatment period is long, and the second peak appears when the first peak has not been completely treated.
At this time, there are two mechanisms at the same time.
Brain inflammation
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Therefore, we can divide CNS infection into 2 stages, 3 cases, 2 stages are infection and post-infection immune-related inflammation, and 3 cases are infection, immunity, infection + immunity
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Different conditions require different treatment methods, but the clinical symptoms are easily confused, which can easily lead to delayed treatment and lead to serious neurological deficits and other poor prognosis
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The diagnosis of CNS infection is more dependent on inspection methods, which can be roughly divided into three types: traditional pathogenic microorganism detection, new diagnostic methods, and advanced technologies such as artificial intelligence technology
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1) Traditional detection of pathogenic microorganisms ① Methods: pathogenic culture and various smears, microscopic examination after staining,
etc.

②Disadvantages: Culture and staining may have a higher positive rate in other systems, but in central nervous system infections, especially in the detection of cerebrospinal fluid, the positive rate is extremely low, not exceeding 10%
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In other words, more than 90% of central nervous system infections cannot be diagnosed with a clear etiology when relying on traditional staining and culture methods
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2) New diagnostic methods ① Methods: various new staining techniques, rapid culture techniques, rapid genetic testing techniques, next-generation sequencing techniques,
etc.

②Advantages: Sensitive, high positive rate
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③ Disadvantages: However, there are false positives and false negatives, which need to be used in combination with clinical manifestations and traditional pathogenic microorganism detection
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3) Advanced technologies such as artificial intelligence technology provide new and excellent methods for the etiological diagnosis of CNS infection
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(1) mNGS detection technology breaks through the bottleneck of clinical pathogen detection Next-generation sequencing (NGS), also known as deep, high-throughput or massively parallel sequencing, is a set of higher-volume, higher-cost compared to next-generation sequencing.
Lower, shorter, more automated sequencing technologies
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Pathogen metagenomic detection (mNGS), without presetting, without culture, without preference, directly extract nucleic acid in the sample, perform NGS, and then compare and analyze with the database to determine the type of pathogenic microorganisms in the sample, which can quickly and objectively detect Pathogenic microorganisms (including viruses, bacteria, fungi, parasites) in clinical samples without specific amplification
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To put it figuratively, conventional methods may be fishing, and NGS is fishing with nets
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Because the space where the cerebrospinal fluid is located is relatively closed, the application of mNGS has opened up a new world.
For example, the mortality rate of meningitis caused by Coccus posadas is close to 100%.
Early detection of pathogenic bacteria and timely treatment are the keys to good prognosis.
mNGS can be used as a tool for early diagnosis.
means
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Professor Peng Fuhua also gave an example of a 36-year-old female inpatient in his hospital with a history of pancreatitis.
The image is shown below
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After discussing for a long time, I didn’t know what it was.
The pathology report showed that it was in line with inflammatory lesions, and I didn’t know what it was
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In the end, it was found to be Aspergillus flavus through mNGS, and through targeted treatment, the effect was very good
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It is worth noting that the cerebrospinal fluid mNGS can also be used for dynamic assessment of efficacy, which is detected before and after treatment
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If the treatment is ineffective, the number of specific sequences increases or changes little; if the treatment is effective, the number of specific sequences decreases; if cured, it is negative
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Moreover, compared with the traditional method, mNGS is very fast, and it may take 18 days of culture to detect the growth of acid-fast bacilli.
However, mNGS only takes 1 day to detect Mycobacterium tuberculosis, and the patient is treated on the 1st day and treated on the 18th day, the prognosis gap As you can imagine
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Therefore, on December 13, 2021, the "Expert Consensus on the Application of Second Generation Sequencing of Cerebrospinal Fluid Metagenomics in Infectious Diseases of the Central Nervous System" was published in the "Chinese Journal of Neurology"
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This is the world's first cerebrospinal fluid mNGS application consensus, highlighting clinical applications, mainly domestic research, and commonly used cerebrospinal fluid specimens.
Welcome to read
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(II) Other new technologies 1) Rapid genetic testing technology: Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome some of the shortcomings of the initial Xpert test, including insufficient sensitivity
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2) Rapid culture technology: With the application of BACTEC-TB960 and BacT ALERT 3D detection system, the positive rate has been improved and the culture time has been shortened
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3) New staining technique: improved Mycobacterium tuberculosis smear
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4) Discover new biomarkers,
etc.

Treatment of CNS Infectious Diseases (1) Treatment of bacterial meningitis ▌ General principles of choosing antibiotics for bacterial meningitis ①Select bactericides that are sensitive to pathogens; ②Select antibiotics that easily penetrate the blood-brain barrier; ③Intravenous antibiotics should be used as soon as possible ; ④ Early combination medication, and then change the drug according to drug sensitivity; ⑤ Large dose, full course of treatment
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Studies have shown that the principles of antibiotic use for severe bacterial meningitis: early, adequate and appropriate
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That is, in the early stage, all possible pathogenic bacteria are widely covered, and once the pathogen is identified, the treatment can be de-escalated
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▌ Adjuvant administration of daptomycin, 2 emerging therapeutic targets for bacterial meningitis: The empiric antibiotic therapy in most suspected ABM centers is the third-generation cephalosporin ceftriaxone
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However, ceftriaxone prolongs destructive inflammation even when the bacteria are killed, and a phase II clinical trial evaluating the insoluble antibiotic daptomycin in adjunctive treatment of pneumococcal meningitis is currently underway (ClinicalTrials.
gov, NCT03480191)
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Adjunctive administration of daptomycin may inhibit the inflammatory effects of ceftriaxone through a currently unknown mechanism
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5 Antagonists: The destructive coagulation and fibrinolytic cascades in the cerebrospinal fluid are triggered by excess complement C5
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Inhibition of C5 improved outcomes in mouse models, and clinical trials of C5 antagonists are currently underway
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(2) Treatment of tuberculous meningitis Drug-resistant Mycobacterium tuberculosis is the main difficulty and the main research point.
It is mainly classified into mono-drug-resistant, multi-drug-resistant, multi-drug-resistant (MDR), and pan-drug-resistant (XDR) Mycobacterium tuberculosis
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The World Health Organization (WHO) guidelines for the treatment of multidrug-resistant tuberculosis stipulate: 1) According to the past drug history and drug resistance test results, it is best to choose 4-5 drugs, of which at least 3 drugs that have never been used, such as curly Mycin (CPM), Fluoroquinolones, Isoniazid (Pa), etc.

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2) The course of treatment can be extended to 18 months
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3) At the same time, various immunotherapy should be added on the basis of effective chemotherapy to improve the curative effect
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Currently commonly used immunotherapy includes IFN-γ, IL-2, thalidomide and so on
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Common compatibility scheme of MDR tuberculosis: isoniazid 300mg/d + rifampicin 450mg/d or 600mg/d + pyrazinamide 25-30mg/d + acetylbutanol 15-20mg/kg/d + moxifloxacin/levofloxacin 400-800mg/d
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Common compatibility scheme of XDR tuberculosis: isoniazid 300mg/d + rifampicin 450mg/d or 600mg/d + pyrazinamide 25-30mg/d + acetylbutanol 15-20mg/kg/d + linezolid 1200mg/d
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Severe cases can also be considered in combination with drugs
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Adjuvant therapy: 1) Drug adjuvant therapy ① Glucocorticoids
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② Immunosuppressants: thalidomide, infliximab, montelukast
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③ aspirin
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2) Cerebrospinal fluid replacement ① The implementation of fluid discharge can further reduce the intracranial pressure of the patient
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②It can reduce the protein concentration in human cerebrospinal fluid, improve the microcirculation of cerebrospinal fluid in patients, and avoid the occurrence of arachnoid adhesions at the base of the skull
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③ Intrathecal injection of anti-tuberculosis drugs such as dexamethasone and isoniazid
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④ Reduce the levels of inflammatory mediators such as TNF-a (tumor necrosis factor), CRP (c-reactive protein), and reduce the body's inflammatory response
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(3) Treatment of cryptococcal meningitis 1) Novel antifungal drug therapy: amphotericin B liposome, voriconazole, posaconazole and oxaconazole
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2) Drug combination therapy: Synergistic combination therapy is an increasingly important strategy to expand the efficacy of currently used drugs
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Combination therapy has the potential to improve efficacy and fungal selectivity
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3) Research and development of new antifungal strategies including targeting gene or cellular functions, blocking virulence factors, inhibiting stress response signaling, employing compound combinations and developing immunomodulatory therapies
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Relevant studies have shown that triple therapy of amphotericin B, fluconazole and 5-flucytosidine may be more effective than dual therapy
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In addition, Professor Peng Fuhua introduced that after more than ten years of research on the disease in other departments, it is believed that classification and staging treatment may be better.
For example, first, according to whether AIDS is combined, the treatment plans and principles are not exactly the same: 1) Non-AIDS related Cryptococcal Meningitis - Clear Cryptococcus
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2) AIDS-Associated Cryptococcal Meningitis - Control of infection, may not clear Cryptococcus
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At the same time, individualized treatment can reduce the length of hospital stay
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▌ Treatment stages and optional drugs 1) Induction (intensive) phase amphotericin B or AMB liposome, 5-FC, fluconazole, voriconazole
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2) Fluconazole and voriconazole in the consolidation phase
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3) Fluconazole and voriconazole in maintenance phase
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For severe patients, studies have shown that triple therapy + VP shunt has better efficacy
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(4) Research on hormones as adjuvant therapy As mentioned above, the treatment of infectious meningitis is divided into 2 stages and 3 cases, and the treatment methods are different
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Differences in the treatment of CNS infections and post-infection immune diseases Therefore, for CNS infections, antibiotics and hormones perform their respective functions, which can achieve twice the result with half the effort and obtain the best curative effect
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1) For the first peak (infectious), the commonly used treatment regimens are as follows: ① Tuberculosis: anti-tuberculosis + 6-8 weeks of hormones
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②Severe viral disease (autoimmune brain? Immune-related encephalitis/myelitis after viral infection?): antiviral + early, massive, short-term hormones
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③ purulent: antibiotics + 2-4 days of hormones
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④ Parasites: Anti-parasites + hormones
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⑤ Treponema: antibiotics + early application of hormones (syphilis for 5 days)
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⑥ Cryptococcus: Immune reconstitution syndrome, cryptococcal encephalopathy, amphotericin side effects and other side effects can be considered hormones
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2) For the second peak (immunity), the commonly used treatment regimens are as follows: If the autoimmune encephalitis antibody is positive: ①Treatment principles and goals Early treatment, immunotherapy, symptomatic treatment (epileptic seizures, mental symptoms, etc.
)
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②The first-line treatment of immunotherapy (hormone plus lgIV or plasma exchange) was changed to second-line treatment (rituximab or cyclophosphamide)
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③ Staged treatment Acute treatment and maintenance treatment (hormone plus azathioprine for at least 1 year to prevent recurrence)
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If autoimmune encephalitis antibodies are negative, such as infectious encephalomyelitis (ADEM), follow the ADEM regimen
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3) Double peaks overlap: infectious + immune etiology is infection + immune abnormality, basic etiology treatment (anti-infection + immunosuppression and regulation), and effective anti-infection based on immunotherapy
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 Key points 1) The relationship between CNS infection and immunity is clear, some CNS infection diseases will evolve into immune diseases, and two different pathogenic and treatment methods should be grasped
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2) Diagnosis of CNS infection: the rapid development of new detection technology, still need to combine traditional detection methods and clinical manifestations 3) CNS infection treatment: from experience to precision; it is necessary to grasp the respective roles of antibiotics and hormones, and classify and treat
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The speaker introduced Professor Peng Fuhua, chief physician, MD, doctoral supervisor, deputy director of the Department of Neurology and director of the neuroinfection subspecialty at the Third Affiliated Hospital of Sun Yat-Sen University
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Visiting Scholar at Johns Hopkins University
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Sponsor of Southern Central Nervous System Infection Alliance, Head of Neuroinfection Group of Neurology Branch of Guangdong Medical Association, Chairman of Central Nervous System Infection Committee of Guangdong Medical Industry Association, Deputy Director of Cerebrovascular Disease Branch of Guangdong Medical Association, Guangdong Province Vice-chairman of the Neuroimmunity and Infection Professional Committee of the Elderly Health Care Association, vice-chairman of the Neurological Difficulty Diseases Professional Committee of the Guangdong Geriatric Health Care Association, member of the Infection and Cerebrospinal Fluid Group of the Neurology Branch of the Chinese Medical Association, and neuroinfection disease of the Neurology Branch of the Chinese Medical Doctor Association Member of the special committee, member of the Standing Committee of the Neurology Management Committee of the Guangdong Medical Industry Association, member of the Professional Committee of Hemorrhagic Stroke Internal Medicine of the Expert Committee on Stroke Prevention and Control of the National Health and Medical Commission, editorial board member of the Journal World of Radiology, Austin Journal of Neurological disorders & Epilepsy, Neuroscience , Journal of medicine and medical sciences, "Chinese Journal of Neurology" and other reviewers, review experts of the National Natural Science Foundation of China
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Presided over and participated in a number of national, provincial and ministerial research projects
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Video playback↓↓↓