Compilation of a self-management assessment scale for postoperative patients with aortic dissection.

Objective: The aim of this research was to compile a self-management assessment scale for patients with aortic dissection (AD). The questionnaire is useful in making the patient aware of the need for post-operative care in order to contribute to improving the outcome and quality of life. Methods: The initial version of the "postoperative self-management assessment scale for patients with aortic dissection" was developed using the Delphi expert consultation method based on qualitative research results, consultation of self-management-related literature, reference to the existing self-management scale, and self-efficacy theory, combined with the disease characteristics of AD. By using the convenience sampling method, a total of 201 patients with AD who had undergone surgery were selected as the research participants. The initial version of the scale was used for follow-up investigation, and the scale entries were evaluated and exploratory factor analysis carried out to form the formal version of the "postoperative self-management assessment scale for patients with aortic dissection." A total of 214 patients with AD after surgery were selected as the research participants. The formal version of the scale was used for follow-up investigation, and its reliability and validity were evaluated. Results: The formal version of the scale had 6 dimensions and 35 entries. The Cronbach's α coefficient for the total scale was 0.908, the split-half reliability was 0.790, and the test-retest reliability after 2 weeks was 0.471. The content validity index of the total scale was 0.963. Exploratory factor analysis yielded six common factors, and the cumulative contribution rate of variance was 66.303%. Confirmatory factor analysis showed that except for the incremental fit index, Tucker-Lewis index, and comparative fit index >0.85, slightly lower than 0.90, χ 2/df <3, root mean square of approximation <0.08, parsimonious goodness-of-fit index, and parsimonious normed fit index >0.50; all other model fitting requirements were satisfied, indicating that the model fitting was acceptable. Conclusion: We compiled the postoperative self-management assessment scale for patients with AD, which has demonstrated excellent reliability and validity and can be used as a tool to evaluate the postoperative self-management level in patients with aortic dissection.

Analysis of serum calcium change trajectories and prognostic factors in patients with acute type A aortic dissection.

OBJECTIVES: This study aimed to analyze the correlation between serum calcium changes and short-term prognosis of patients with acute type A aortic dissection. METHODS: Patients who underwent acute type A aortic dissection surgery at Fujian Heart Medical Center between June 2019 and June 2021 were retrospectively analyzed. RESULTS: A total of 383 patients were enrolled. According to the changing track of serum calcium in patients after acute type A aortic dissection, three potential category tracks were determined: high-level (n = 85), medium-level (n = 259), and continuous low-level groups (n = 39). Using the medium-level group as the control, regression analysis showed that poor prognosis risk was increased in the group with continuous low serum calcium (odds ratio = 2.454, P < 0.05) and in the group with continuous low serum calcium > 48 h (odds ratio = 3.595, P < 0.05). Age (odds ratio = 1.063, P < 0.001), body mass index (odds ratio = 1.138, P < 0.05), hypertension (odds ratio = 3.697, P < 0.05), and the highest lactic acid within 72 h after surgery(odds ratio = 1.093, P < 0.05) were independent risk factors for poor prognosis after aortic dissection. CONCLUSION: Continuous low serum calcium was an independent predictor of poor prognosis in patients with acute type A aortic dissection.

Cytokine Storm in Acute Viral Respiratory Injury: Role of Qing-Fei-Pai-Du Decoction in Inhibiting the Infiltration of Neutrophils and Macrophages through TAK1/IKK/NF-[Formula: see text]B Pathway.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Pancreatic neuroendocrine tumor detected by technetium-99m methoxy-2-isobutylisonitrile single photon emission computed tomography/computed tomography: A case report.

BACKGROUND: Pancreatic neuroendocrine tumors (NETs) account for about 1%-2% of pancreatic tumors and about 8% of all NETs. Computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasound are common imaging modalities for the diagnosis of pancreatic NETs. Furthermore, somatostatin receptor imaging is of great value for diagnosing pancreatic NETs. Herein, we report the efficacy of technetium-99m methoxy-2-isobutylisonitrile (99mTc-MIBI) single photon emission CT (SPECT)/CT for detecting pancreatic NETs. CASE SUMMARY: A 57-year-old woman presented to our hospital with a 1-d history of persistent upper abdominal distending pain. The distending pain in the upper abdomen was aggravated after eating, with nausea and retching. Routine blood test results showed a high neutrophil percentage, low leukomonocyte and monocyte percentages, and low leukomonocyte and eosinophil counts. Amylase, liver and kidney function, and tumor markers alpha-fetoprotein, carcinoembryonic antigen, and cancer antigen (CA) 125, CA72-4, CA19-9, and CA153 were normal. Abdominal CT showed a mass, with multiple calcifications between the pancreas and the spleen. The boundary between the mass and the pancreas and spleen was poorly defined. Contrast-enhanced CT revealed that the upper abdominal mass was unevenly and gradually enhanced. 99mTc-MIBI SPECT/CT revealed that a focal radioactive concentration, with mild radioactive concentration extending into the upper abdominal mass, was present at the pancreatic body and tail. The 99mTc-MIBI SPECT/CT manifestations were consistent with the final pathological diagnosis of pancreatic NET. CONCLUSION: 99mTc-MIBI SPECT/CT appears to be a valuable tool for detecting pancreatic NETs.

TG/HDL-C ratio predicts in-hospital mortality in patients with acute type A aortic dissection.

BACKGROUND: In recent years, abnormalities in serum lipids and lipoproteins have been shown to be associated with cardiovascular disease risk. However, their prognostic value for acute type A aortic dissection is unclear. This study analyzed the correlation between triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio and in-hospital mortality in patients with AAAD, and aimed to investigate the clinical significance of preoperative blood lipids and lipoproteins on the prognosis of acute type A aortic dissection. METHODS: A total of 361 patients who underwent type A aortic dissection surgery in Fujian Cardiac Medical Center from June 2018 to March 2020 were retrospectively collected. According to the baseline TG/HDL-C ratio, the patients were divided into 3 groups according to the tertile method, the low TG/HDL-C ratio T1 group (< 1.18) and the middle TG/HDL-C ratio T2 group (1.18-1.70). T3 group with high TG/HDL-C ratio (> 1.70). Kaplan-Meier was used for survival analysis, and Cox proportional hazards regression model was used to analyze the factors affecting the prognosis of patients. The receiver operating characteristic (ROC) curve was used for the diagnostic efficacy. RESULTS: Among the 361 patients in this study, the mean age was 52.4 ± 11.3 years, 73 (20.2%) were female, and 82 (22.7%) died in hospital. Kaplan-Meier curve showed that with the increase of TG/HDL-C ratio, the risk of in-hospital death gradually increased (P < 0.001). Multivariate Cox regression analysis showed that age (HR = 1.031), body mass index (HR = 1.052), hypertension (HR = 3.491), white blood cells (HR = 1.073), TG/HDL-C ratio (HR = 1.604), MODS (HR = 1.652) was positively correlated with in-hospital mortality (P < 0.05). After adjusting for age, sex, and other risk factors, a significant association was found between the TG/HDL-C ratio and in-hospital mortality for acute type A aortic dissection (HR = 1.472, 95% CI, 1.354-3.451, P = 0.019). CONCLUSION: Patients with type A aortic dissection have obvious abnormal blood lipid metabolism, and serum TG/HDL-C levels are positively correlated with in-hospital mortality in patients with AAAD.

Effects of chewing gum on gastrointestinal function in patients following spinal surgery: a meta-analysis and systematic review.

PURPOSE: There are conflicting opinions regarding the efficacy of chewing gum for the recovery of gastrointestinal function in patients following spinal surgery. Thus, we aimed to conduct a systematic review and meta-analysis of existing articles to evaluate the effect of gum-chewing on patients following spinal surgery. METHODS: A computer search was used to identify randomised controlled trials (RCTs) involving gum-chewing from eight databases: Cochrane Library, PubMed, Embase, MEDLINE, Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database, and WanFang Data. After evaluating the risk of bias for the included studies, we used the Revman 5.3 software to conduct a meta-analysis of the data. RESULTS: The study included seven RCTs, with a total of 706 patients. The meta-analysis reported that gum-chewing could shorten the interval between surgery and first bowel movement (mean deviation [MD] = - 23.02; 95% confidence interval [CI]: - 24.67, - 21.38; P < 0.00001), first flatus (MD = - 1.54; 95% CI - 2.48, - 0.60; P = 0.001), and first bowel sounds (MD = - 5.08; 95% CI - 6.02, - 4.15; P < 0.00001). Moreover, there was a significant reduction in postoperative analgesic dosage within 12 h (standardised mean difference [SMD] = - 0.28; 95% CI - 0.52, - 0.05; P = 0.02). However, there were no significant differences between the chewing gum and control groups (P > 0.05) regarding the postoperative nausea score, abdominal pain score, 24- and 48-h analgesic drug dosage, and length of hospital stay. CONCLUSION: To a certain extent, masticating gum can promote the recovery of gastrointestinal function and reduce the need for postoperative analgesics in patients following spinal surgery. However, this conclusion is affected by the quantity and quality of the included articles. Therefore, additional high-quality studies are needed to verify these results.

Efficacy and Safety of Oral Hydration 1 Hour After Extubation of Patients Undergoing Cardiac Surgery: A Randomized Controlled Trial.

BACKGROUND: Thirst is one of the most common and uncomfortable symptoms in patients after cardiac surgery. The postextubation time for early oral hydration (EOH) remains unclear, and there is a lack of studies on its safety and effectiveness. OBJECTIVE: The aim of this study was to investigate the effects of oral hydration 1 hour after extubation on thirst, salivary pH, salivary flow, oral mucosa, halitosis, gastrointestinal adverse reactions, aspiration pneumonia, and satisfaction in patients undergoing cardiac surgery. METHODS: Eighty-four patients who underwent cardiac surgery were randomly assigned into 2 groups, for either conventional oral hydration (COH) or EOH. The EOH group drank 30 mL of warm water 1 hour post extubation and thereafter 50 mL hourly for 4 hours. The COH group had nil per os for 4 hours after extubation. If no dysphagia was evident after 4 hours, the patients were instructed to slowly drink water. Thirst intensity was evaluated every hour before the intervention. Nausea and vomiting were recorded after drinking water. The salivary pH, unstimulated salivary flow rate, oral odor, and oral mucosal moisture were evaluated at 1 hour post extubation, immediately before the intervention, and at 4 hour post intervention. Aspiration pneumonia data were collected within 72 hours post intervention. Satisfaction was assessed before leaving the intensive care unit. RESULTS: The scores for thirst (3.38 ± 1.04; F = 306.21, P < .001), oral mucosa (2.03 ± 0.74; P < .001), and halitosis (2.77 ± 0.63; P < .001) in the EOH group were significantly lower than those in the COH group. The EOH group had significantly higher salivary pH (6.44 ± 1.06; P < .001), unstimulated salivary flow rates (0.18 ± 0.08; P < .001), and patient satisfaction (4.28 ± 0.45; P < .001) than the COH group. Nausea and vomiting did not differ significantly between groups (P = .60). Aspiration pneumonia was not observed in either group. CONCLUSIONS: Oral hydration 1 hour after extubation significantly alleviated thirst and stabilized the oral environment without gastrointestinal adverse reactions or aspiration pneumonia, and with increased patient satisfaction.

Association between circulating CD39+CD8+ T cells pre-chemoradiotherapy and prognosis in patients with nasopharyngeal carcinoma.

BACKGROUND: The mortality rate among patients with nasopharyngeal carcinoma (NPC) has improved significantly with the advent of chemoradiotherapy strategies. However, distant metastasis remains problematic. Tumor-specific reactivity in cancer patients has been detected exclusively in CD39+ T cells, particularly in CD39+CD103+ T cells. Circulating cancer-specific T cells are important for protecting against metastasis. This study aimed to evaluate the predictive value of circulating CD39+CD8+ T cells for metastasis in patients with NPC. METHODS: We performed a cross-sectional, longitudinal study of 55 patients with newly diagnosed NPC of stage III-IVa. All patients were initially treated with standard combined chemoradiotherapy. Blood samples were obtained from 24 patients before and at 1 month and 6 months after treatment. T cell expression of CD39 and CD103, together with the markers of T cell exhaustion programmed death-1 (PD-1)/T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and markers of cell differentiation CD27/CC-chemokine receptor 7/CD45RA, was examined by flow cytometry. The Wilcoxon rank-sum test analysis was used to analyze the differences between two groups. Kaplan-Meier analysis was used for analysis of progression-free survival (PFS). RESULTS: The expression of circulating CD39+CD8+ and CD39+CD103+ CD8+ T cells was significantly higher in patients without distant metastasis (CD39+CD8+: 6.52% [1.24%, 12.58%] vs. 2.41% [0.58%, 5.31%], Z=-2.073, P=0.038 and CD39+CD103+CD8+: 0.72% [0.26%, 2.05%] vs. 0.26% [0.12%, 0.64%], Z=-2.313, P = 0.021). Most CD39+ T cells did not express PD-1 or Tim-3. Patients with high expression of CD39+CD103+CD8+ T cells had better PFS than patients with low expression (log rank value = 4.854, P = 0.028). CD39+CD8+ T cells were significantly elevated at 1-month post-treatment (10.02% [0.98%, 17.42%] vs. 5.91% [0.61%, 10.23%], Z = -2.943, P = 0.003). The percentage of advanced differentiated CD8+ T cells also increased at 1-month post-treatment compared with pre-treatment (33.10% [21.60%, 43.05%] vs. 21.00% [11.65%, 43.00%], Z = -2.155, P = 0.031). There was a significant correlation between elevated CD39+CD8+ T cells and increased effector memory T cells (intermediate stage: r = 0.469, P = 0.031; advanced stage: r = 0.508, P = 0.019). CONCLUSIONS: CD39+CD8+ circulating T cells have preserved effector function, contributing to an improved prognosis and a reduced risk of metastasis among NPC patients. These cells may thus be a useful predictive marker for a better prognosis in patients with NPC.

Association between glucose variability and postoperative delirium in acute aortic dissection patients: an observational study.

BACKGROUND: Blood glucose variability is associated with poor prognosis after cardiac surgery, but the relationship between glucose variability and postoperative delirium in patients with acute aortic dissection is unclear. The study aims to investigate the association of blood glucose variability with postoperative delirium in acute aortic dissection patients. METHODS: We prospectively analyzed 257 patients including 103 patients with delirium. The patients were divided into two groups according to whether delirium was present. The outcome measures were postoperative delirium, the length of the Intensive Care Unit stay, and the duration of hospital stay. Multivariable Cox competing risk survival models was used to assess. RESULTS: A total of 257 subjects were enrolled, including 103 patients with delirium. There were statistically significant differences between the two groups in body mass index, history of cardiac surgery, first admission blood glucose, white blood cell counts, Acute Physiology and Chronic Health Evaluation II score, hypoxemia, mechanical ventilation duration, and the length of Intensive Care Unit stay(P < 0.05). The delirium group exhibited significantly higher values of the mean of blood glucose (MBG) and the standard deviation of blood glucose (SDBG) than in the non-delirium group(P < 0.05). In model 1, the adjusted hazard ratio (AHR) of the standard deviation of blood glucose was 1.436(P < 0.05). In Model 2, the standard deviation of blood glucose (AHR = 1.418, 95%CI = 1.195-1.681, P < 0.05) remained significant after adjusting for confounders. The area under the curve of the SDBG was 0.763(95%CI = 0.704-0.821, P < 0.01). The sensitivity was 81.6%, and the specificity was 57.8%. CONCLUSIONS: Glucose variability is associated with the risk of delirium in patients after aortic dissection surgery, and high glycemic variability increases the risk of postoperative delirium.

Human Leukocyte Antigen-A Allele Distribution in Nasopharyngeal Carcinoma Patients Showing Anti-Melanoma-Associated Antigen A or Synovial Sarcoma X-2 T Cell Response in Blood.

BACKGROUND: Development of innovative immunotherapy is imperative to improve the poor survival of the nasopharyngeal carcinoma (NPC) patients. In this study, we evaluated the T cell response to melanoma-associated antigen (MAGE)-A1, MAGE-A3, or synovial sarcoma X-2 (SSX-2) in the peripheral blood of treatment-naive NPC patients. The relationship of responses among the three proteins and the human leukocyte antigen (HLA)-A types were analyzed to provide evidence of designing novel therapy. METHODS: Sixty-one NPC patients admitted into the Tumor Hospital affiliated to the Xinjiang Medical University between March 2015 and July 2016 were enrolled. Mononuclear cells were isolated from the peripheral blood before any treatment. HLA-A alleles were typed with Sanger sequence-based typing technique. The T cell response to the MAGE-A1, MAGE-A3, or SSX-2 was evaluated with the Enzyme-Linked ImmunoSpot assay. Mann-Whitney U-test was used to compare the T cell responses from different groups. Spearman's rank correlation was used to analyze the relationship of T cell responses. RESULTS: HLA-A*02:01, A*02:07, and A*24:02 were the three most frequent alleles (18.9%, 12.3%, and 11.5%, respectively) among the 22 detected alleles. 31.1%, 19.7%, and 16.4% of the patients displayed MAGE-A1, MAGE-A3, or SSX-2-specific T cell response, respectively. The magnitudes of response to the three proteins were 32.5, 38.0, and 28.7 SFC/106 peripheral blood mononuclear cells, respectively. The T cell response against the three proteins correlated with each other to different extent. The percentage of A*02:01 and A*24:02 carriers were significantly higher in patients responding to any of the three proteins compared to the nonresponders. CONCLUSION: MAGE-A1, MAGE-A3, or SSX-2-specific T cell responses were detectable in a subgroup of NPC patients, the frequency and magnitude of which were correlated.

HLA-A*02-B*46 haplotype: an adverse prognostic factor in Han patients with nasopharyngeal carcinoma.

Epidemiological studies have shown that human leukocyte antigen (HLA) allelic polymorphisms are closely correlated to susceptibility to nasopharyngeal carcinoma (NPC), and in a previous study, we showed that HLA-B*46 and HLA-A*02-B*46 haplotypes were strongly associated with NPC susceptibility. In this retrospective study, we investigated the phenotype of the HLA-A and HLA-B alleles and haplotypes and correlated these data to the clinical and pathological parameters of NPC to understand the role of HLA alleles and haplotypes in NPC prognosis. The cohort comprised 117 NPC patients from a Han population in Xinjiang. The local recurrence-free survival (LRFS), distant metastasis- free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were analyzed. The 5-year DMFS of the HLA-A*02-B*46 haplotype carriers and non-carriers was 66.4% and 90.3%, respectively. In addition, age was found to be a prognostic factor for LRFS, DFS, and OS (P=0.032, 0.040, and 0.013, respectively). We found that the HLA-A*02-B*46 haplotype might be a prognostic marker in addition to the traditional TNM staging in patients with NPC.

A Comprehensive Analysis of the Impact of HIV on HCV Immune Responses and Its Association with Liver Disease Progression in a Unique Plasma Donor Cohort.

OBJECTIVE: Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) co-infection is recognized as a major cause of morbidity and mortality among HIV-1 infected patients. Our understanding of the impact of HIV infection on HCV specific immune responses and liver disease outcome is limited by the heterogeneous study populations with genetically diverse infecting viruses, varying duration of infection and anti-viral treatment. METHODS: Viral-specific immune responses in a cohort of 151 HCV mono- and HIV co-infected former plasma donors infected with a narrow source of virus were studied. HCV and HIV specific T cell responses were correlated with clinical data. RESULTS: HIV-1 accelerated liver disease progression and decreased HCV specific T cell immunity. The magnitude of HCV specific T cell responses inversely correlated with lower HCV RNA load and reduced liver injury as assessed by non-invasive markers of liver fibrosis. HIV co-infection reduced the frequency of HCV specific CD4+ T cells with no detectable effect on CD8+ T cells or neutralizing antibody levels. CONCLUSION: Our study highlights the impact of HIV co-infection on HCV specific CD4+ T cell responses in a unique cohort of patients for both HCV and HIV and suggests a crucial role for these cells in controlling chronic HCV replication and liver disease progression.

Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals.

The SNP rs12252-C allele alters the function of interferon-induced transmembrane protein-3 increasing the disease severity of influenza virus infection in Caucasians, but the allele is rare. However, rs12252-C is much more common in Han Chinese. Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.

[Spatial distribution characteristics of NMHCs during winter haze in Beijing].

NMHCs and NOx samples were simultaneously collected and analyzed in six urban and suburban representative sampling sites (Sihuan, Tian'anmen, Pinguoyuan, Fatou, Beijing Airport and Miyun) during a typical haze period in winter 2005, Beijing. The concentrations of NMHCs during the sampling period in descending order were: Sihuan (1101.29 microg x m(-3)) > Fatou (692.40 microg x m(-3)) >Tian'anmen (653.28 microg x m(-3)) >Pinguoyuan (370.27 microg x m(-3)) > Beijing Airport (350.36 microg x m(-3)) > Miyun (199.97 microg x m(-3)). Atmospheric benzene pollution in Beijing was rather serious. The ratio of NMHCs/NOx ranged from 2.1 to 6.3, indicating that the peak ozone concentrations in urban Beijing were controlled by VOCs during the sampling period. Analysis of propylene equivalent concentration and ozone formation potential showed that the NMHCs reactivity descended in the order of Sihuan > Fatou > Tian'anmen > Pinguoyuan > Beijing Airport > Miyun. B/T values (0.52 to 0.76) indicated that besides motor vehicle emission, coal combustion and other emission sources were also the sources of NHMCs in Beijing in winter. The spatial variations of isoprene in Beijing indicated that the contribution of anthropogenic sources to isoprene increased and the emissions by biogenic sources decreased in winter. The spatial variations of propane and butane indicated that LPG emissions existed in the urban region of Beijing.

High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection.

RATIONALE: T-cell responses have been implicated in control and exacerbation of lung injury during influenza A virus (IAV) infection. OBJECTIVES: To examine the breadth and magnitude of influenza-specific CD4(+) and CD8(+) T-cell responses during acute phase of infection. METHODS: Influenza-specific T-cell response to the entire pandemic H1N1/09 IAV proteome and T cell-related cytokine levels were measured in blood from previously healthy individuals with mild (n = 32) and severe (n = 16) IAV infection during the 2009 influenza pandemic. Virus-specific T-cell response in lung and blood was also performed in two acutely infected, severely ill patients using fluorescent-conjugated pdmH1N1/09 Matrix-MHC-I tetrameric complexes. MEASUREMENTS AND MAIN RESULTS: Strong and broad CD4(+) but not CD8(+) T-cell responses were observed in the blood, and were higher in those with severe disease. Antigen-specific CD8(+) T cells in the lungs were on average 45-fold higher compared with blood in severely ill patients. Paradoxically, in patients with severe disease, IL-17, IL-2, IL-4, and IFN-γ levels were significantly decreased. CONCLUSIONS: High levels of circulating virus-specific CD4(+) T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection are associated with subsequent development of severe IAV infection. This finding could be an early and specific marker for ensuing clinical deterioration. Contrasting levels of antigen-specific CD8(+) T cells in lungs and blood have implications on design and analysis of clinical trials for T-cell vaccines because measurements of T cells in the periphery may not reflect events in the lungs.

HLA-B may be more protective against HIV-1 than HLA-A because it resists negative regulatory factor (Nef) mediated down-regulation.

Human leukocyte antigen HLA-B alleles have better protective activity against HIV-1 than HLA-A alleles, possibly due to differences in HLA-restricted HIV-1-specific CD8+ cytotoxic T lymphocyte (CTL) function, but the mechanism is unknown. HIV-1 negative regulatory factor (Nef) mediates down-regulation of surface expression of class I HLA (HLA-I) and may therefore impair immune recognition by CTL. Because of sequence differences in the cytoplasmic domains, HLA-A and -B are down-regulated by Nef but HLA-C and -E are not affected. However, the latter are expressed at low levels and are not of major importance in the CTL responses to HIV-1. Here, we compared the role of the cytoplasmic domains of HLA-A and -B in Nef-mediated escape from CTL. We found HLA-B cytoplasmic domains were more resistant to Nef-mediated down-regulation than HLA-A cytoplasmic domains and demonstrated that these differences affect CTL recognition of virus-infected cells in vitro. We propose that the relative resistance to Nef-mediated down-regulation by the cytoplasmic domains of HLA-B compared with HLA-A contributes to the better control of HIV-1 infection associated with HLA-B-restricted CTLs.

Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation.

T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyse infected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (KD) of the TCR-pMHC complex determines the response, whereas the "productive hit rate model" suggests that the off-rate (koff) is critical. Here, we used mathematical modeling to show that antigen potency, as determined by the EC50 (half-maximal effective concentration), which is used to support KD-based models, could not discriminate between the affinity and the productive hit rate models. Both models predicted a correlation between EC50 and KD, but only the productive hit rate model predicted a correlation between maximal efficacy (Emax), the maximal T cell response induced by pMHC, and koff. We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Thus, we propose that the activity of an antigen is determined by both its potency (EC50) and maximal efficacy (Emax).

Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals.

The threat of avian influenza A (H5N1) infection in humans remains a global health concern. Current influenza vaccines stimulate antibody responses against the surface glycoproteins but are ineffective against strains that have undergone significant antigenic variation. An alternative approach is to stimulate pre-existing memory T cells established by seasonal human influenza A infection that could cross-react with H5N1 by targeting highly conserved internal proteins. To determine how common cross-reactive T cells are, we performed a comprehensive ex vivo analysis of cross-reactive CD4+ and CD8+ memory T cell responses to overlapping peptides spanning the full proteome of influenza A/Viet Nam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals from the United Kingdom and Viet Nam. Memory CD4+ and CD8+ T cells isolated from the majority of participants exhibited human influenza-specific responses and showed cross-recognition of at least one H5N1 internal protein. Participant CD4+ and CD8+ T cells recognized multiple synthesized influenza peptides, including peptides from the H5N1 strain. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition. In addition, cross-reactive CD4+ and CD8+ T cells recognized target cells infected with recombinant vaccinia viruses expressing either H5N1 M1 or NP. Thus, vaccine formulas inducing heterosubtypic T cell-mediated immunity may confer broad protection against avian and human influenza A viruses.

Transition from long-term nonprogression to HIV-1 disease associated with escape from cellular immune control.

Transition from long-term nonprogressive infection to progressive HIV-1 disease presents an opportunity to investigate pathogenesis in a defined immunogenetic background. We studied a male long-term nonprogressor (LTNP) who remained asymptomatic and viremic and had normal CD4 T-cell counts without antiretroviral therapy for >18 years and then experienced a transition to disease progression. We analyzed the complete HIV-1 genomic RNA sequence from plasma and cellular immune responses to predefined human leukocyte antigen-matched autologous viral peptides spanning the viral genome, before and after progression. Serial viral sequences did not seem attenuated and consistently utilized coreceptor CCR5. LTNP status was associated with elongated V2 domains and broad low-level T-cell immune responses targeting several regions of the viral genome. The transition to progressive disease was associated with the acquisition of viral mutations conferring escape from CD8 T-cell responses. Multiple changes in HIV-1 sequence and loss of immune response over time most likely contributed to the transition from LTNP status to progressive disease. These data are relevant to vaccine design and identification of the correlates of protection from disease progression.