Critical role of the gut microbiota in immune responses and cancer immunotherapy.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

Current clinical findings of acute neurological syndromes after SARS-CoV-2 infection.

Neuro-COVID, a condition marked by persistent symptoms post-COVID-19 infection, notably affects various organs, with a particular focus on the central nervous system (CNS). Despite scant evidence of SARS-CoV-2 invasion in the CNS, the increasing incidence of Neuro-COVID cases indicates the onset of acute neurological symptoms early in infection. The Omicron variant, distinguished by heightened neurotropism, penetrates the CNS via the olfactory bulb. This direct invasion induces inflammation and neuronal damage, emphasizing the need for vigilance regarding potential neurological complications. Our multicenter study represents a groundbreaking revelation, documenting the definite presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of a significant proportion of Neuro-COVID patients. Furthermore, notable differences emerged between RNA-CSF-positive and negative patients, encompassing aspects such as blood-brain barrier integrity, extent of neuronal damage, and the activation status of inflammation. Despite inherent limitations, this research provides pivotal insights into the intricate interplay between SARS-CoV-2 and the CNS, underscoring the necessity for ongoing research to fully comprehend the virus's enduring effects on the CNS. The findings underscore the urgency of continuous investigation Neuro-COVID to unravel the complexities of this relationship, and pivotal in addressing the long-term consequences of COVID-19 on neurological health.

Genetic and phenotypic analyses of PRRT2 positive and negative paroxysmal kinesigenic dyskinesia.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 (PRRT2) are the most common genetic cause of PKD. Objective: The objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations. Methods: We enrolled 219 PKD patients, documented their clinical information and performed PRRT2 screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without PRRT2 variants. Genotype-phenotype correlation analyses were conducted on the probands. Results: Among 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 PRRT2 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without PRRT2 variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% versus 8.99%, respectively). Patients with truncated PRRT2 variants tend to have bilateral attacks. We identified two transmembrane protein 151A (TMEM151A) variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD. Conclusion: These findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated PRRT2 variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of PRRT2 and TMEM151A variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.

Quality indicators for epilepsy management in China: The development of a tool to assess care and first three-year report.

OBJECTIVES: Epilepsy care in China has expanded considerably in the last decade but still remains largely unknown; we developed an easy-to-use tool to assess its quality. METHODS: We adapted the Epilepsy Update Quality Measurement, produced by the American Academy of Neurology (AAN) for use in China: The Quality Indicator for Epilepsy Treatment-China National Action (QUIET-CHINA). This tool incorporates a standardized case report form initially for logging quality indicators for people with epilepsy during in-patient stays. Nine quality indicators covered seizures, drugs, diagnostics, screening for co-morbid conditions, counseling for woman of child bearing age, and a composite indicator was further proposed by total number of interventions performed divided by the total number of people eligible in each indicator. The tool also has an electronic reporting and data feedback system. 96 epilepsy centers in 31 jurisdictions in mainland China have been piloted since 2017. RESULTS: Data from 11,600 individuals with epilepsy in the first 3-year study period were analyzed. The median age was 31; 60% were male. The composite indicators were 74%. Seizure freedom rate was less than 25% in all epilepsy types and post-surgical seizure freedom rate was 21%. 90% had seizure type and frequency, antiepileptic drugs recorded, while only 70% with active epilepsy were on regular antiepileptic drugs treatment. Investigations for diagnosis and etiology were performed in around 90% but screening for co-morbid conditions and counseling for women of childbearing potential was 38% and 15% respectively. Severe side effect happened in 2% individuals during the treatment. CONCLUSION: The preliminary results of the national action provided some baseline information. Except for an overall improvement, a significant treatment gap still exists, and psychiatric co-morbidities or issues affecting women are not seen as a priority. QUIET-CHINA will be expanded to more and other levels of hospitals, to help narrow the treatment gap and equalize the comprehensive epilepsy care on the national level.

Neurological complications during the Omicron COVID-19 wave in China: A cohort study.

BACKGROUND AND PURPOSE: The aim was to investigate the neurological complications associated with coronavirus disease 19 (COVID-19) during the 2022 Omicron wave. METHODS AND ANALYSIS: The medical records of a cohort of people admitted to neurological wards of three participating tertiary centres in Sichuan from 12 December 2022 to 12 January 2023 were reviewed. Demographics and clinical data were obtained and analysed with an interest in COVID-19-related new-onset or worse neurological symptoms. The current data were also compared in two centres with similar data from the same period 12 months earlier. RESULTS: In all, 790 people were enrolled, of whom 436 were positive for COVID-19. Ninety-nine had new onset COVID-related neurological problems, or their known neurological condition deteriorated during the wave. There was a significant difference in demographics from the findings amongst admissions 12 months earlier as there was an increase in the average age, the incidence of encephalitis and encephalopathy, and mortality rates. One hundred and one received COVID-specific antivirals, intravenous glucocorticoids and intravenous immunoglobulin therapy. No differences were seen between these and those who did not use them. CONCLUSION: New-onset neurological conditions, particularly encephalitis and encephalopathy, increased significantly during this period. Deterioration of existing neurological conditions, such as seizure exacerbation, was also observed. A large-scale treatment trial of people with COVID-19 infection presenting with neurological disorders is still needed.

The initial treatment in convulsive status epilepticus in China: A multi-center observational study.

OBJECTIVE: To investigate the initial treatment of patients with convulsive status epilepticus (CSE) in a resource-limited region of China, and to discuss the difference of in-hospital outcomes and economic costs between those with guideline-recommended initial treatment and those without. METHODS: In this retrospective study, we screened adult patients discharged with the diagnosis of CSE in four centers in west China. Individuals with different exposure to the initial drug were divided into benzodiazepine (BDZ) and non-BDZ group for outcome comparison. The primary outcomes were seizure control, and the ratio of patients who developed refractory SE. The secondary outcomes included in-hospital mortality, the modified Rankin Scale (mRS) score at discharge, in-hospital respiratory support rate, length, and cost of the stay. RESULTS: Three-hundred and thirteen patients (127, 40.6% were women) with CSE were included. The median age was 43 (range 16-92). There were 152 (48.6%) patients initially treated with BDZ. Among the 36 who received midazolam as initial treatment, twenty-six received an insufficient dose. The other 116 (76.3%) patients in the BDZ group chose diazepam as initial treatment. Fifteen of them (12.9%) were treated underdose. In the non-BDZ group (161, 51.4%), antiseizure medications (ASMs) and/or coma-induced drugs were used as initial treatment. Among those initially administrated ASMs, intramuscular phenobarbital (38,37.6%) and valproate (46, 52.3%) were most frequently seen. There was a significant difference in the time latency to initial treatment and etiology between BDZ and non-BDZ group. The non-BDZ group reported a higher cessation rate after initial treatment compared to the BDZ group (P = 0.012). No significant difference in other primary and secondary outcomes. SIGNIFICANCE: Non-adherence and underdosing of the initial treatment of SE were common in China. However, the non-BDZ group showed a better seizure control rate. The effect came from early aggressive medication, that is, the combination of ASMs and anesthesia. Non-BDZ group was not inferior to BDZs in terms of seizure control, the occurrence of in-hospital death, and poor outcome at discharge. More robust evidence is needed in developing settings when choosing the initial treatment.

Crucial role of the transcription factors family activator protein 2 in cancer: current clue and views.

The transcription factor family activator protein 2 (TFAP2) is vital for regulating both embryonic and oncogenic development. The TFAP2 family consists of five DNA-binding proteins, including TFAP2A, TFAP2B, TFAP2C, TFAP2D and TFAP2E. The importance of TFAP2 in tumor biology is becoming more widely recognized. While TFAP2D is not well studied, here, we mainly focus on the other four TFAP2 members. As a transcription factor, TFAP2 regulates the downstream targets directly by binding to their regulatory region. In addition, the regulation of downstream targets by epigenetic modification, posttranslational regulation, and interaction with noncoding RNA have also been identified. According to the pathways in which the downstream targets are involved in, the regulatory effects of TFAP2 on tumorigenesis are generally summarized as follows: stemness and EMT, interaction between TFAP2 and tumor microenvironment, cell cycle and DNA damage repair, ER- and ERBB2-related signaling pathway, ferroptosis and therapeutic response. Moreover, the factors that affect TFAP2 expression in oncogenesis are also summarized. Here, we review and discuss the most recent studies on TFAP2 and its effects on carcinogenesis and regulatory mechanisms.

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review.

OBJECTIVE: Genes associated with Long QT syndromes (LQTS), such as KCNQ1, KCNH2, and SCN5A, are common causes of epilepsy. The Arg 744* variant of KCNH2 has been previously reported in people with epilepsy or LQTS, but none of these patients were reported to simultaneously suffer from epilepsy and LQTS. Herein, we report the case of a family with epilepsy and cardiac disorders. METHOD: The proband, a 25-year-old woman, with a family history of epilepsy and LQTS was followed at West China Hospital. The proband experienced her first seizure at the age of seven. Video electroencephalograms (vEEGs) showed epileptic discharges. Her 24-h dynamic electrocardiograms 2 (ECGs) showed QTc prolongation. The proband's mother, who is 50 years old, had her first generalized tonic-clonic seizure (GTCS) at the age of 18 years old. After she gave birth at the age of 25, the frequency of seizures increased, so antiepileptic therapy was initiated. When she was 28 years old, she complained of palpitations and syncope for the first time, and QTc prolongation was detected on her 24-h dynamic ECGs. The proband's grandmother also had complaints of palpitations and syncope at the age of 73. Her 24-h dynamic ECGs indicated supraventricular arrhythmia, with the lowest heart rate being 41 bpm, so she agreed to a pacemaker. Considering the young patient's family history, blood samples of the patient and her parents were collected for genetic analysis. RESULTS: A heterozygous variant of KCNH2 [c.2230 (exon9) C>T, p. Arg744Ter, 416, NM_000238, rs189014161] was found in the proband and her mother. According to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we classified the KCNH2 variant as pathogenic. SIGNIFICANCE: This study expands the clinical phenotype of the Arg 744* KCNH2 pathogenic variant. In the context of channelopathies, because of the genetic susceptibility of the brain and the heart, the risk of comorbidity should be considered. This also indicates the importance of precise antiepileptic drug (AED) management and regular ECG monitoring for patients with channelopathies.

Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.

Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their ß-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.

Long-Term Prognosis of Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis Who Underwent Teratoma Removal: An Observational Study.

Objective: This study aimed to evaluate the clinical characteristics and long-term surgical outcomes of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with teratoma. Methods: Patients who were admitted to West China Hospital from June 2012 to June 2019 and diagnosed with anti-NMDAR encephalitis were enrolled in the study. Medical records were reviewed prospectively to gather clinical characteristic data. Patients were followed up at long-term every 3 months. Results: This study included 192 patients, among whom 21 (10.9%) were detected with having a teratoma. Patients included 20 women, with a mean age of 24.62 ± 7.61 years. Seizure and psychiatric symptoms were the most dominant symptoms in both groups, followed by memory deficits. Central hypoventilation (52.4 vs. 17%, p < 0.001) and decreased consciousness (71.4 vs. 31.3%, p = 0.002) were significantly more frequent in patients with teratoma than in those without. Moreover, the anti-NMDAR antibody titer was higher (p = 0.021) and the baseline modified Rankin scale score was lower (p = 0.004) in patients with teratoma than in those without. First-line immunotherapy was performed in 21 (100%) patients with teratoma and 167 (97.7%) patients without teratoma. All patients with teratoma had the tumor removed. During follow-up, two (9.5%) patients with teratoma and 11 (6.4%) patients without teratoma died, whereas 1 (4.8%) patient with teratoma and 37 (21.6%) patients without teratoma had relapses. Overall, 19 (90.5%) patients with teratoma and 151 (88.3%) patients without teratoma achieved favorable clinical outcomes at the final follow-up. Conclusions: With early detection and removal of teratoma, most patients with anti-NMDAR encephalitis and teratoma achieved a favorable long-term prognosis.

COVID-19 vaccine take-up rate and safety in adults with epilepsy: Data from a multicenter study in China.

OBJECTIVE: This study was undertaken to investigate the COVID-19 vaccine uptake rate and possible postvaccination effects in adults with epilepsy. METHODS: We invited adults with epilepsy attending three centers in China from July 24 to August 31, 2021 to participate in this study. We also asked age- and sex-matched controls among people attending for other chronic neuropsychiatric conditions and healthy controls accompanying people with illness attending the hospitals to participate. We excluded people who, under the national guidelines, had evident contradictions to vaccination. Participants were interviewed face-to-face using questionnaires. Vaccine uptake and postvaccine adverse events among the people with epilepsy were compared with those with neuropsychiatric conditions and controls. We also compared the willingness and reasons for hesitancy among unvaccinated participants. RESULTS: We enrolled 981 people, of whom 491 had epilepsy, 217 had other neuropsychiatric conditions, and 273 were controls. Forty-two percent of those with epilepsy had had the first dose of a vaccine, compared with 93% of controls and 84% of the people with neuropsychiatric conditions (p < .0001). The majority (93.8%) of those immunized had inactivated vaccines. Among the unvaccinated people with epilepsy, 59.6% were willing to have the vaccine. Their main reasons for hesitation were potential adverse effects (53.3%) and concerns about losing seizure control (47.0%). The incidence of adverse events in the epilepsy group was similar to controls. Nineteen people with epilepsy reported an increase in seizure frequency. No episode of status epilepticus or prolonged seizures was reported. Two controls had their first-ever seizure, which was unlikely related to the vaccine. SIGNIFICANCE: The vaccine uptake rate in people with epilepsy was lower than in their same-age controls. The postvaccination effect was no higher than in controls. We found no evidence suggesting worsening seizures after vaccination. Measurement and education focused on increasing the vaccination rate in epilepsy are warranted.

Rehabilitative management of pelvic fractures needs to be further optimized.

We read with interest the review by Piccione et al. into the rehabilitative management of patients with pelvic fracture (PF). This review adds to our knowledge about the significance and indispensability of early multidisciplinary intervention in PF. From our perspective, however, potential bias might be caused by several unanswered questions. The uncertain methodological process and the unclear definition could misguide the rehabilitation strategies while still in dispute. Therefore, further high-quality studies should be conducted to optimize the multidisciplinary rehabilitation of patients with PF.

Potent neutralizing RBD-specific antibody cocktail against SARS-CoV-2 and its mutant.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor-binding domain (RBD)-specific antibodies from mice through vaccination with a recombinant SARS-CoV-2 RBD. RBD-targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS-CoV-2 neutralization. High-affinity RBD-specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS-CoV-2 viruses and the SARS-CoV-2 pseudovirus particle containing the spike protein S-RBDV367F mutant (SARS-CoV-2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I-IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS-CoV-2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD-specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS-CoV-2 and its isolates.

Reduction of Retinal Thickness Ipsilateral to Hippocampal Sclerosis in Epilepsy.

Objectives: Reductions in the peripapillary retinal nerve fiber layer (pRNFL) have been reported in epilepsy, namely in drug-resistant people. Hippocampal sclerosis (HS) is the most frequent cause of drug-resistant epilepsy in tertiary care centers. We aimed to evaluate the likelihood and characteristic of RNFL loss in individuals with epilepsy having HS. Methods: Fifty-five adults diagnosed with unilateral HS (mean age of 25 years; 42 female) by magnetic resonance imaging were included in this observational cross-sectional study, 58 age-matched individuals with epilepsy with no detectable structural brain abnormality were included as non-HS, and 55 people without neurological diseases were included as healthy controls. pRNFL of both eyes was measured by optical coherence tomography (OCT). In each individual disease related information was recorded. Results: Among the 55 individuals with unilateral HS, one (1.82%) and ten (18.18%) had significant or borderline abnormal thinning of the pRNFL of the ipsilateral eye to the HS. The average pRNFL ipsilateral to the side of HS was significantly thinner than people with epilepsy non-HS (p = 0.013) and healthy controls (p = 0.000), especially in the inferior quadrants. Only age was significantly correlated with the average and inferior quadrant pRNFL thickness of the ipsilateral eye to the HS (R = -0.286, p = 0.035; R = -0.353, p = 0.008 respectively). Conclusion: These preliminary findings suggest that retinal abnormalities associated with HS may have a specific pattern. Further studies need to confirm this finding and to unravel the underlying mechanism.

Association of consciousness impairment and mortality in people with COVID-19.

BACKGROUND: To investigate the association between impairment of consciousness and risk of death in people with COVID-19. METHODS: In this multicentre retrospective study, we enrolled people with confirmed COVID-19 from 44 hospitals in Wuhan and Sichuan, China, between 18 January and 30 March 2020. We extracted demographics, clinical, laboratory data and consciousness level (as measured by the Glasgow Coma Scale (GCS) score) from medical records. We used Cox proportional hazards regression, structural equation modelling and survival time analysis to compare people with different progressions of impaired consciousness. RESULTS: We enrolled 1,143 people (average age 51.3 ± standard deviation 17.1-year-old; 50.3% males), of whom 76 died. Increased mortality risk was identified in people with GCS score between 9 and 14 (hazard ratio (HR) 46.76, p < .001) and below 9 (HR 65.86, p < .001). Pathway analysis suggested a significant direct association between consciousness level and death. Other factors, including age, oxygen saturation level and pH, had indirect associations with death mediated by GCS scores. People who developed impaired consciousness more rapidly either from symptoms onset (<10 days vs. 10-19 days, p = .025, <10 days vs. ≥20 days and 10-19 days vs. ≥20 days, <.001) or deterioration of oxygen saturation (≤2 days vs.>2 days, p = .028) had shorter survival times. CONCLUSION: Altered consciousness and its progression had a direct link with death in COVID-19. Interactions with age, oxygen saturation level and pH suggest possible pathophysiology. Further work to confirm these findings explore prevention strategies and interventions to decrease mortality is warranted.

The potential neurological effect of the COVID-19 vaccines: A review.

The coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic with people infected in almost all countries. The most efficient solution to end this pandemic is a safe and efficient vaccine. Classic platforms are used to develop vaccines including live-attenuated vaccine, inactivated vaccine, protein subunit vaccine, and viral vector. Nucleic acid vaccine uses next-generation platforms for their development. Vaccines are now rushing to the market. Eleven candidates are in advance development. These comprise inactivated vaccines, viral vector vaccine, nucleic acid vaccine, and the protein subunit vaccine platform, which are now quite advanced in trials in various geographic and ethnic populations. The reported severe adverse effects raised the worries about their safety. It becomes critical to know whether these vaccines will cause neurologic disorders like previously recognized vaccine-related demyelinating diseases, fever-induced seizure, and other possible deficits. We reviewed the most promising COVID-2 vaccines with a particular interest in mechanism(s) and adverse effect(s). We exemplify potential neurological problems these vaccines could cause by looking at previous studies. The current evidence indicated a minor risk of the acute neurological disorders after the application. The observation of the long-time effect is still needed.