Clinical heterogeneity of NLRP12-associated autoinflammatory diseases.

Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in NLRP12 cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far, very few patients with NLRP12-AID have been identified worldwide; therefore, data on the clinical phenotype and genetic profile are limited. In this study, we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of NLRP12, including 2 novel null mutations. Of the patients, some with same mutations showed different clinical features. Compared to healthy controls, the increased levels of cytokines were revealed in the patients' plasmas, as well as in the supernatants of patients' cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression; but decreased level of NLRP12 protein was shown in the null mutations. And in vitro expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively, this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum, and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice, especially for patients presenting with periodic fever but no other genetic cause identified.

Risk factors for cytomegalovirus infection and disease after kidney transplantation: A meta-analysis.

OBJECTIVE: To investigate the risk factors for cytomegalovirus (CMV) infection and disease in kidney transplantation recipient, and provide references for the prevention and control of CMV infection and disease in kidney transplantation patients. METHODS: Chinese and international literature related to risk factors for CMV infection and disease in renal transplant recipients was searched using databases, including China National Knowledge Infrastructure; WanFang Data; Wiper; Chinese Biomedical Literature database; PubMed; Embase; Web of Science, and the Cochrane Register of Controlled Trials. Two researchers independently screened the literature, extracted the data, and evaluated the quality of the literature according to published standards. A meta-analysis was performed using RevMan 5.4 software to extract the risk factors for CMV infection and disease in renal transplant recipients. RESULTS: A total of 59,847 subjects were included in 24 studies. The risk factors for CMV infection were ATG [OR = 2.76, 95% CI (2.10, 3.63), P < 0.00001], Donor (D) CMV-IgG(+) Receptor (R)(-): (D+/R-) [OR = 2.97, 95% CI (1.63, 5.44), P = 0.004 < 0.05], recipient age [OR = 1.96, 95% CI (1.50, 2.54), P < 0.00001], lymphocytopenia [OR = 3.26, 95% CI (1.46, 7.31), P < 0.00001], and mycophenolate [OR = 3.22, 95% CI (2.02, 5.46), P < 0.00001]. The protective factor for CMV infection was glomerular filtration rate (GFR) [OR = 0.98, 95% CI (0.97, 0.99), P < 0.00001], and the uncertain factors were the use of tacrolimus [OR = 0.91, 95% CI (0.64, 1.28), P = 0.58 > 0.05], rejection [OR = 1.32, 95% CI (0.49, 3.53), P = 0.58 > 0.05], donor age [OR = 1.00, 95% CI (0.99, 1.01), P = 0.67 > 0.5], and preemptive therapy [OR = 0.51, 95% CI (0.11, 2.36), P = 0.86 > 0.05]. The risk factors for CMV disease were D+/R- [OR = 4.78, 95% CI (3.76, 6.07), P < 0.00001], ATG [OR = 1.83, 95% CI (1.25, 2.67), P < 0.00001], rejection [OR = 1.42, 95% CI (1.26, 1.59), P < 0.00001], mycophenolate [OR = 1.67, 95% CI (1.38, 2.02), P < 0.00001], recipient age [OR = 1.03, 95% CI (1.02, 1.03), P < 0.00001], donor age [OR = 1.01, 95% CI (1.00, 1.01), P = 0.001 < 0.05], Donor (D) CMV-IgG(+) Receptor(R)(+): (D+/R+) [OR = 1.92, 95% CI (1.49, 2.46), P < 0.00001], the use of prednisolone [OR = 1.59, 95% CI (1.32, 1.92), P < 0.00001], and diabetes mellitus[OR = 1.18, 95% CI (1.01, 1.37), P = 0.03 < 0.05], and the uncertain factors were donor type [OR = 4.10, 95% CI (0.28, 59.79), P = 0.30 > 0.05], time of transplantation [OR = 0.95, 95% CI (0.78, 1.16), P = 0.64 > 0.05], and the use of cyclosporine [OR = 1.50, 95% CI (0.62, 3.64), P = 0.37 > 0.05]. CONCLUSION: There are many factors influencing CMV infection and disease in kidney transplant patients. Risk factors should be carefully monitored, protective factors strengthened, and more attention paid to uncertain factors.

A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Onset Interstitial Lung Disease.

Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) mutations cause early-onset immune dysregulation syndrome, characterized by multi-organ autoimmunity and lymphoproliferation. Of them, interstitial lung disease (ILD) usually develops after the involvement of other organs, and the onset time is childhood and beyond rather than infancy. Here, we reported a patient who presented with fatal infancy-onset ILD, finally succumbing to death. Next-generation sequencing identified a novel heterozygous mutation in STAT3 (c.989C>G, p.P330R). Functional experiments revealed it was a gain-of-function mutation. Upon interleukin 6 stimulation, this mutation caused a much higher activation of STAT3 than the wild-type control. In addition, the mutation also activated STAT3 under the steady state. The T helper 17 cell level in the patient was significantly higher than that in normal controls, which may contribute to the autoimmune pathology caused by the STAT3P330R mutation. Apart from Janus kinase (JAK) inhibitors, we also provided experimental evidence of a STAT3 selective inhibitor (Stattic) effectively suppressing the activation of mutant STAT3 in vitro. Collectively, our study expanded the clinical spectrum of STAT3 GOF syndrome. STAT3 GOF mutation appears as a new etiology of ILD and should be considered in patients with early-onset ILDs. In addition to JAK inhibitors, the specific STAT3 inhibitor would be an appealing option for the targeted treatment.

A comparison of Knowledge, attitude and practice (KAP) of nurses on nursing Post-stroke dysphagia patients between iii-A and ii-A hospitals in China: a propensity score-matched analysis.

BACKGROUND: Whether knowledge, attitude and practice of nurses on nursing post-stroke dysphagia patients varies between different ranking hospitals is still unknown. This study aimed to compare the knowledge, attitude and practice level of nurses on nursing post-stroke dysphagia patients between iii-A and ii-A hospitals in China. DESIGN: A cross-sectional study design was used. METHODS: Data were collected from eighteen hospitals in Wuhan, Hubei in May-July 2020, and a total of 824 nurses were recruited by convenient sampling. After propensity score matching, 205 participants in iii-A hospitals were matched with 205 participants in ii-A hospitals. RESULTS: There were no statistically differences in the socio-demographic characteristics between two groups after propensity score matching. Before matching, the regression coefficients between hospital ranking and knowledge, attitude, practice were -0.415, -0.718 and -1.855, respectively. After matching, the coefficients changed to -0.394, -0.824 and -1.278. Nurses from iii-A hospitals had higher knowledge and attitude scores than nurses from ii-A hospitals, but no significant practice scores difference was observed between various rankings of hospitals. CONCLUSIONS: The KAP of nurses on nursing post-stroke dysphagia patients were different in iii-A and ii-A hospitals. Administrators should strengthen management, provide more learning resources and trainings to meet nurses' needs about methods to deal with and recognize dysphagia, so as to further improve the quality of post-stroke dysphagia management.

Efficacy and Safety of Anti-TNFα Therapy for Uveitis Associated with Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis.

INTRODUCTION: To investigate the efficacy and safety of anti-TNFα therapy in patients with juvenile idiopathic arthritis associated uveitis (JIA-U). METHODS: Embase, PubMed, Cochrane Library, and Web of Science were systematically searched for studies reporting anti-TNFα treatment in patients with JIA-U. The primary outcome was the control of intraocular inflammation (CII). The pooled proportion of CII was assessed by the random-effects method when I2 > 50%, otherwise, by the fixed-effect method. This study was registered with PROSPERO (CRD42020161749). RESULTS: Three randomized clinical trials (RCTs), twelve case series, three retrospective cohort studies, and three case reports were identified. A total of 399 patients were receiving anti-TNFα therapy, of which 201 patients were treated with adalimumab (ADA), 139 with infliximab (IFX), 36 with etanercept (ETA), 20 with golimumab (GLM), and 3 with certolizumab pegol (CZP). The pooled proportions of CII on observational studies were 82% (95% CI 63-96%) in patients receiving ADA, 56% (95% CI 30-80%) in IFX, 38% (95% CI 8-73%) in ETA and 65% (95% CI 42-86%) in GLM, respectively. All three patients treated with CZP reached improved activity. ADA therapy led to a significantly higher proportion of CII compared to IFX therapy (χ2 = 26.24, P < 0.001), or to ETA therapy (χ2 = 13.43, P < 0.001); but no statistical difference was observed between IFX and ETA (χ2 = 0.13, P = 0.71). As to safety, most reported adverse events were tolerable and two cohort studies consistently showed that ADA was safer than IFX. CONCLUSIONS: The existing evidence suggests that ADA is better than IFX regarding efficacy and safety. The effectiveness of IFX is higher than ETA with no statistical difference. GLM and CZP may be proxies for ADA but the evidence is limited.

[Clinical and immunological studies on neonatal infectious pneumonia].

OBJECTIVE: To explore etiology, clinical manifestation and immunological changes of infectious pneumonia of neonates in Chengdu area. METHODS: Serum specimens were collected from 111 infants with infectious pneumonia. Eight viral and mycoplasmal specific serum IgM antibodies were detected by enzyme linked immunosorbent assay (ELISA); C reactive protein (CRP), total IgG and its subclasses, IgA and IgM were determined by rate scattered nephelometry; T lymphocyte subpopulations were detected by biotin-streptavidin-peroxidase method, and clinical and other laboratory data were analyzed. RESULTS: (1) Etiological agents: specific serum IgM antibodies were positive in 40 of 111 cases (36.0%) with pneumonias. All the 30 control infants were negative for the specific serum IgM antibodies. Among 111 infants with infectious pneumonia, 20.7% had single viral or mycoplasmal infection, 40.5% had bacterial infection, 15.3% had viral and mycoplasmal infection with bacterial infection; 23.4% had infection with unknown agents. (2) The most common clinical manifestations were tachypnea and cyanosis. The next were cough, milk choking, rales, retractions of the supraclavicular, intercostal and subcostal areas. Roentgenographic examination commonly revealed vague opacities, increased density and patchy infiltration. (3) Immune status: (1) CD(3), CD(4) cell counts of infants with pneumonias were lower than those of the controls while their serum IgA, IgM concentrations were higher than those of the control. (2) The CD(3) and CD(4) cell counts of the group with bacterial infection were lower than those of the control group. (3) The serum IgA concentration of the group with viral and mycoplasmal infection was higher than those of the control group and the group with unknown infection. (4) The serum IgM concentration of the group with bacterial infection was higher than those of the control group. (5) There were no significant differences in CD(8) cell counts, CD(4)/CD(8), concentration of serum IgG and IgG(1 - 4) between pneumonia group and the control group, and among various infectious groups and the control. CONCLUSION: Pathogens of neonatal infectious pneumonia in Chengdu area included single viral or mycoplasmic infection or bacterial infection, viral and mycoplasmal infection with bacterial infection, and unknown infection. Immunological changes of newborn infants suffered from infectious pneumonia included declined CD(3) and CD(4) cell counts, particularly in bacterial infection.