Commensal bacteria inhibit viral infections via a tryptophan metabolite.

There is growing appreciation that commensal bacteria impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Studying a simian-human immunodeficiency virus (SHIV)-challenged cohort of pediatric nonhuman primates, we bioinformatically associated Lactobacillus gasseri and the bacterial family Lachnospiraceae with enhanced resistance to infection. We experimentally validated these findings by demonstrating two different Lachnospiraceae isolates, Clostridium immunis and Ruminococcus gnavus, inhibited HIV replication in vitro and ex vivo. Given the link between tryptophan catabolism and HIV disease severity, we found that an isogenic mutant of C. immunis that lacks the aromatic amino acid aminotransferase (ArAT) gene, which is key to metabolizing tryptophan into 3-indolelactic acid (ILA), no longer inhibits HIV infection. Intriguingly, we confirmed that a second commensal bacterium also inhibited HIV in an ArAT-dependent manner, thus establishing the generalizability of this finding. In addition, we found that purified ILA inhibited HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that the AhR has been implicated in the control of multiple viral infections, we demonstrated that C. immunis also inhibited human cytomegalovirus (HCMV) infection in an ArAT-dependent manner. Importantly, metagenomic analysis of individuals at-risk for HIV revealed that those who ultimately acquired HIV had a lower fecal abundance of the bacterial ArAT gene compared to individuals who did not, which indicates our findings translate to humans. Taken together, our results provide mechanistic insights into how commensal bacteria decrease susceptibility to viral infections. Moreover, we have defined a microbiota-driven antiviral pathway that offers the potential for novel therapeutic strategies targeting a broad spectrum of viral pathogens.

Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody breadth.

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female rabbits with monovalent (gB-1), bivalent (gB-1+gB-3), or pentavalent (gB-1+gB-2+gB-3+gB-4+gB-5) gB lipid nanoparticle-encapsulated nucleoside-modified RNA (mRNA-LNP) vaccines. The multivalent vaccine groups did not demonstrate a higher magnitude or breadth of the IgG response to the gB ectodomain or cell-associated gB compared to that of the monovalent vaccine. Also, the multivalent vaccines did not show an increase in the breadth of neutralization activity and antibody-dependent cellular phagocytosis against HCMV strains encoding distinct gB genotypes. Interestingly, peripheral blood mononuclear cell-derived gB-2-specific T-cell responses elicited by multivalent vaccines were of a higher magnitude compared to that of monovalent vaccinated animals against a vaccine-mismatched gB genotype at peak immunogenicity. Yet, no statistical differences were observed in T cell response against gB-3 and gB-5 variable regions among the three vaccine groups. Our data suggests that the inclusion of multivalent gB antigens is not an effective strategy to increase the breadth of anti-HCMV gB antibody and T cell responses. Understanding how to increase the HCMV vaccine protection breadth will be essential to improve the vaccine efficacy.

CXCL9 as a Reliable Biomarker for Discriminating Anti-IFN-γ-Autoantibody-Associated Lymphadenopathy that Mimics Lymphoma.

The diagnosis of adult-onset immunodeficiency syndrome associated with neutralizing anti-interferon γ autoantibodies (AIGA) presents substantial challenges to clinicians and pathologists due to its nonspecific clinical presentation, absence of routine laboratory tests, and resemblance to certain lymphoma types, notably nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI). Some patients undergo lymphadenectomy for histopathological examination to rule out lymphoma, even in the absence of a preceding clinical suspicion of AIGA. This study aimed to identify reliable methods to prevent misdiagnosis of AIGA in this scenario through a retrospective case-control analysis of clinical and pathological data, along with immune gene transcriptomes using the NanoString nCounter platform, to compare AIGA and nTFHL-AI. The investigation revealed a downregulation of the C-X-C motif chemokine ligand 9 (CXCL9) gene in AIGA, prompting an exploration of its diagnostic utility. Immunohistochemistry (IHC) targeting CXCL9 was performed on lymph node specimens to assess its potential as a diagnostic biomarker. The findings exhibited a significantly lower density of CXCL9-positive cells in AIGA compared to nTFHL-AI, displaying a high diagnostic accuracy of 92.3% sensitivity and 100% specificity. Furthermore, CXCL9 IHC demonstrated its ability to differentiate AIGA from various lymphomas sharing similar characteristics. In conclusion, CXCL9 IHC emerges as a robust biomarker for differentiating AIGA from nTFHL-AI and other similar conditions. This reliable diagnostic approach holds the potential to avert misdiagnosis of AIGA as lymphoma, providing timely and accurate diagnosis.

Vaccination with a replication-defective cytomegalovirus vaccine elicits a glycoprotein B-specific monoclonal antibody repertoire distinct from natural infection.

Human Cytomegalovirus (HCMV) is the leading infectious congenital infection globally and the most common viral infection in transplant recipients, therefore identifying a vaccine for HCMV is a top priority. Humoral immunity is a correlate of protection for HCMV infection. The most effective vaccine tested to date, which achieved 50% reduction in acquisition of HCMV, was comprised of the glycoprotein B protein given with an oil-in-water emulsion adjuvant MF59. We characterize gB-specific monoclonal antibodies isolated from individuals vaccinated with a disabled infectious single cycle (DISC) CMV vaccine, V160, and compare these to the gB-specific monoclonal antibody repertoire isolated from naturally-infected individuals. We find that vaccination with V160 resulted in gB-specific antibodies that bound homogenously to gB expressed on the surface of a cell in contrast to antibodies isolated from natural infection which variably bound to cell-associated gB. Vaccination resulted in a similar breadth of gB-specific antibodies, with binding profile to gB genotypes 1-5 comparable to that of natural infection. Few gB-specific neutralizing antibodies were isolated from V160 vaccinees and fewer antibodies had identifiable gB antigenic domain specificity compared to that of naturally-infected individuals. We also show that glycosylation of gB residue N73 may shield binding of gB-specific antibodies.

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model.

Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.

The pentameric complex is not required for vertical transmission of cytomegalovirus in seronegative pregnant rhesus macaques.

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neonatal neurological impairment but essential virological determinants of transplacental CMV transmission remain unclear. The pentameric complex (PC), composed of five subunits, glycoproteins H (gH), gL, UL128, UL130, and UL131A, is essential for efficient entry into non-fibroblast cells in vitro . Based on this role in cell tropism, the PC is considered a possible target for CMV vaccines and immunotherapies to prevent cCMV. To determine the role of the PC in transplacental CMV transmission in a non-human primate model of cCMV, we constructed a PC-deficient rhesus CMV (RhCMV) by deleting the homologues of the HCMV PC subunits UL128 and UL130 and compared congenital transmission to PC-intact RhCMV in CD4+ T cell-depleted or immunocompetent RhCMV-seronegative, pregnant rhesus macaques (RM). Surprisingly, we found that the transplacental transmission rate was similar for PC-intact and PC-deleted RhCMV based on viral genomic DNA detection in amniotic fluid. Moreover, PC-deleted and PC-intact RhCMV acute infection led to similar peak maternal plasma viremia. However, there was less viral shedding in maternal urine and saliva and less viral dissemination in fetal tissues in the PC-deleted group. As expected, dams inoculated with PC-deleted RhCMV demonstrated lower plasma IgG binding to PC-intact RhCMV virions and soluble PC, as well as reduced neutralization of PC-dependent entry of the PC-intact RhCMV isolate UCD52 into epithelial cells. In contrast, binding to gH expressed on the cell surface and neutralization of entry into fibroblasts by the PC-intact RhCMV was higher for dams infected with PC-deleted RhCMV compared to those infected with PC-intact RhCMV. Our data demonstrates that the PC is dispensable for transplacental CMV infection in our non-human primate model. One Sentence Summary: Congenital CMV transmission frequency in seronegative rhesus macaques is not affected by the deletion of the viral pentameric complex.

Biomechanical analysis of tibial plateau posterolateral fracture fragment fixation and introduction of a lateral tibia plateau hook plate system.

BACKGROUND: Fixing the posterolateral fragments of tibial plateau fractures has been challenging owing to potential neurovascular injuries and fibular head blocks. Several surgical approaches and fixation techniques have been reported, with distinct limitations. We propose a novel lateral tibia plateau hook plate system and compare its biomechanical stability with other fixation methods. METHODS: Twenty-four synthetic tibia models were simulated to present posterolateral tibial plateau fractures. These models were randomly assigned to three groups. Group A models were fixed with the lateral tibia plateau hook plate system, Group B with variable-angle anterolateral locking compression plates, and Group C with direct posterior buttress plates. The models' biomechanical stability was evaluated using static (gradually increased axial compressive loads) and fatigue (cyclically loaded from 100 to 600 N for 2000 cycles each) tests. RESULTS: Groups A and C models exhibited comparable axial stiffness, subsidence load, failure load, and displacement in the static test. Group A model exhibited higher subsidence and failure loads than Group B model. Groups A and C models exhibited comparable displacement at 100 N cyclic loading in the fatigue test. Group C model was more stable at higher loads. Group C model endured the highest subsidence cycle numbers, followed by Groups A and B models. CONCLUSIONS: The lateral tibia plateau hook plate system provided similar static biomechanical stability as the direct posterior buttress plates and comparable dynamic stability under limited axial loading. This system is a potential posterolateral treatment choice owing to its convenience and safety, in treating tibia plateau fractures.

Designing an anatomical contour titanium 3D-printed oblique lumbar interbody fusion cage with porous structure and embedded fixation screws for patients with osteoporosis.

This study aimed to design an anatomical contour metal three-dimensional (3D)-printed oblique lateral lumbar interbody fusion (OLIF) cage with porous (lattices) structure and embedded screw fixation to enhance bone ingrowth to reduce the risk of cage subsidence and avoid the stress-shielding effect. Finite element (FE) analysis and weight topology optimization (WTO) were used to optimize the structural design of the OLIF cage based on the anatomical contour morphology of patients with osteoporosis. Two oblique embedded fixation screws and lattice design with 65% porosity and average pore size of 750 µm were equipped with the cage structure. The cage was fabricated via metal 3D printing, and static/dynamic compression and compressive-shear tests were performed in accordance with the ASTM F2077-14 standard to evaluate its mechanical resistance. On FE analysis, the OLIF cage with embedded screw model had the most stability, lowest stress values on the endplate, and uniform stress distribution versus standalone cage and fixed with lateral plate under extension, lateral flexion, and rotation. The fatigue test showed that the stiffnesses/endurance limits (pass 5 million dynamic test) were 16,658 N/mm/6000 N for axial load and 19,643 N/mm/2700 N for compression shear. In conclusion, an OLIF cage with embedded fixation screws can be designed by integrating FE and WTO analysis based on the statistical results of endplate morphology. This improves the stability of the OLIF cage to decrease endplate destruction. The complex contour and lattice design of the OLIF cage need to be manufactured via metal 3D printing; the dynamic axial compression and compressive-shear strengths are greater than that of the U.S. Food and Drug Administration (FDA) standard.

Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model.

Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n=15), CD4+ T cell-depleted with (n=6) and without (n=6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.

Species distribution and antifungal susceptibility of clinical Aspergillus isolates: A multicentre study in Taiwan, 2016-2020.

BACKGROUND: Epidemiological knowledge is important to guide antifungal therapy. OBJECTIVE: This multicentre study aimed to investigate the species distribution and antifungal susceptibility of Aspergillus isolates in Taiwan. METHOD: Four hundred and ninety-two clinical Aspergillus isolates, collected during 2016-2020, were identified by calmodulin sequencing and tested for antifungal susceptibility using CLSI M38-A3. The Cyp51A sequences of azole-resistant Aspergillus fumigatus and Aspergillus flavus isolates were analysed. RESULTS: This collection comprised 30 species from eight Aspergillus sections-Flavi (33.5%), Nigri (26.0%), Fumigati (24.2%), Terrei (10.0%), Nidulantes (5.1%), Circumdati (0.8%), Restricti (0.2%) and Aspergillus (0.2%). Sections Fumigati, Flavi and Terrei were primarily represented by A. fumigatus (99.2%), A. flavus (95.8%) and A. terreus (100%), respectively. Section Nigri comprised nine species, mostly A. welwitschiae (60.2%), A. niger (12.5%), A. brunneoviolaceus (10.9%) and A. tubingensis (10.2%). A. fumigatus (39.6%) and A. flavus (26.4%) predominated among 53 isolates from lower respiratory samples, whereas section Nigri species (46.2%) and A. terreus (29.2%) predominated among 65 isolates from ear samples. Reduced susceptibility to amphotericin B (minimal inhibitory concentration (MIC) > 1 µg/mL) was noted in A. flavus (7.0%), A. terreus (6.1%), A. nidulans and section Circumdati (A. flocculosus, A. subramanianii and A. westerdijkiae) isolates. Acquired azole resistance was observed in seven A. fumigatus (5.9%), all of which carried TR34 /L98H or TR34 /L98H/S297T/F495I mutation, and three A. flavus (1.9%), one of which carried G441S mutation. Reduced susceptibility to itraconazole (MIC >1 µg/mL) was noted in 55.5% of section Nigri isolates, mainly in A. welwitschiae, A. niger and A. tubingensis, whereas A. brunneoviolaceus, A. aculeatinus and A. japonicus were hypersusceptible to azoles. Anidulafungin was active against all isolates except for one isolate. CONCLUSIONS: This study depicted the molecular epidemiology and species-specific characteristics of Aspergillus in Taiwan, which aids in appropriate antifungal therapy and underlines the need of speciation and susceptibility testing of disease-causing Aspergillus.

End-of-life upcycling of polyurethanes using a room temperature, mechanism-based degradation.

A major challenge in developing recyclable polymeric materials is the inherent conflict between the properties required during and after their life span. In particular, materials must be strong and durable when in use, but undergo complete and rapid degradation, ideally under mild conditions, as they approach the end of their life span. We report a mechanism for degrading polymers called cyclization-triggered chain cleavage (CATCH cleavage) that achieves this duality. CATCH cleavage features a simple glycerol-based acyclic acetal unit as a kinetic and thermodynamic trap for gated chain shattering. Thus, an organic acid induces transient chain breaks with oxocarbenium ion formation and subsequent intramolecular cyclization to fully depolymerize the polymer backbone at room temperature. With minimal chemical modification, the resulting degradation products from a polyurethane elastomer can be repurposed into strong adhesives and photochromic coatings, demonstrating the potential for upcycling. The CATCH cleavage strategy for low-energy input breakdown and subsequent upcycling may be generalizable to a broader range of synthetic polymers and their end-of-life waste streams.

Fabrication of Aluminum Oxide Thin-Film Devices Based on Atomic Layer Deposition and Pulsed Discrete Feed Method.

This study demonstrates the low-temperature (<100 °C) process for growing a thin silica buffer layer and aluminum oxide by atomic layer deposition (ALD) in the same reaction chamber. Heterogeneous multilayer thin films are prepared by a dual-mode equipment based on atomic layer deposition and plasma-enhanced chemical vapor deposition (PECVD) techniques. The pulse discrete feeding method (DFM) was used to divide the precursor purging steps into smaller intervals and generate discrete feeds, which improved the saturated distribution of gas precursors, film density and deposition selectivity. The experimental results show that the process method produces a uniform microstructure and that the best film uniformity is ±2.3% and growth rate is 0.69 Å/cycle. The thickness of aluminum oxide film has a linear relationship with the cyclic growth number from 360 to 1800 cycles. Meanwhile, the structural and mechanical stress properties of aluminum oxide thin films were also verified to meet the requirements of advanced thin-film devices.

Epidemiology, clinical features, and outcomes of strongyloidiasis in Taiwan from 1988 to 2020: A case series and literature review.

OBJECTIVES: We described a case of Strongyloides hyperinfection syndrome, reported a case series, and reviewed published cases of strongyloidiasis in Taiwan. METHODS: Confirmed cases of strongyloidiasis at the National Taiwan University Hospital (NTUH) and NTUH Hsin-Chu Branch from 1988 to 2020 were identified in the medical record database. Literature search was carried out through Pubmed, Google Scholar, and Index to Taiwan Periodical Literature System to identify published cases of strongyloidiasis in Taiwan from 1979 to 2020. Data pertaining to the demographics, underlying medical conditions, clinical manifestations, laboratory findings, and outcomes were extracted. RESULTS: A total of 117 cases of strongyloidiasis were identified, including 20 previously unpublished cases from the two hospitals and 97 published cases in the literature. Overall, 85 (73%) were male and the mean age was 64 years (range, 6-95 years). Classical symptoms such as diarrhea, cough, and skin rash were only observed in 43%, 37%, and 18% of the patients, respectively, whereas eosinophilia at presentation was only found in 48%. Strongyloides hyperinfection syndrome and disseminated strongyloidiasis were identified in 41 (35%) and 4 (3%) patients, respectively. Four (3%) patients had concurrent meningitis. In univariable analysis, being older and having pre-existing chronic obstructive pulmonary disease or asthma were associated with hyperinfection or dissemination (p = 0.024 and 0.003, respectively). The mortality rate was 43% among those with hyperinfection or disseminated infection. CONCLUSIONS: Strongyloidiasis can cause serious complications and mortality. Efforts to diagnose strongyloidiasis early are urgently needed to improve the outcome of patients with strongyloidiasis in Taiwan.

Phylogenetic characteristics of Non-SARS human coronavirus in southern Taiwan, 2012-2013.

This study characterizes the phylogenetic relatedness of non-SARS human coronaviruses (HCoVs) in southern Taiwan by sequencing the nucleocapsid (N), spike (S), and RNA-dependent RNA polymerase (RdRp) genes directly from ten HCoV PCR-positive respiratory samples collected during 2012-2013. In the N, S1, and RdRp phylogeny, HCoV-OC43 in one and three samples was clustered with genotypes F and G, respectively, and HCoV-OC43 in sample YC101/TWN/2013 represented a recombination event between genotypes F and G. Amino acid substitutions in the S1 protein of HCoV-OC43 were also identified. In the N phylogeny, HCoV-HKU1 in one and two samples clustered with genotypes A and B, respectively, and HCoV-229E in two samples was clustered with genogroup 6. The genotypes and genogroup detected here were in line with the prevalent phylogenetic lineages reported outside of Taiwan during the contemporary period. In summary, three species of non-SARS HCoVs with different genotypes cocirculated in the community, with genetic evolution observed in HCoV-OC43.

The influence of students' sense of social connectedness on prosocial behavior in higher education institutions in Guangxi, China: A perspective of perceived teachers' character teaching behavior and social support.

The objective of this study is to examine the sense of social connectedness (SSC) and prosocial behavior (PB) of students in Guangxi higher education institutions in China and to further understand the factors influencing PB of higher education students. In this study, a total of 1,007 students were sampled from 8 Guangxi higher vocational schools through purposive sampling using questionnaires, of which 676 (67.1%) were male students and 331 (32.9%) were female students. This study further enriches self-determination theory by exploring the effects of teachers' character teaching behaviors and social support on PB, using the SSC as an intrinsic motivation. In addition, the results of the study revealed that SSC, perceived teacher character teaching behaviors and perceived social support (PSS) were positively related to students' PB. SSC affects PB not only directly, but also indirectly through the mediating role of perceived teacher character teaching behavior and perceived teacher support. Teacher character teaching behaviors and PSS also play a chain mediating role in the relationship between SSC and PB. Finally, this study provides strategies to optimize school character management for higher education students in order to meet their basic psychological needs and thus promote the production of PB.

Dose caffeinated energy drink is a consideration issue for endurance performance.

Caffeinated energy drinks are commonly taken to improve exercise performance, but there are few studies on the influence of different doses on an athlete's performance. We conducted a double-blind, randomized, counter-balanced, and crossover research study to examine the effects of low caffeinated energy drink (Low ED) or high caffeinated energy drink (High ED) supplement on the performance, haematological response, and oxidative stress in triathletes. Twelve male participants underwent three testing sessions separated by weekly intervals, consisting of sprint triathlon training (0.75 km swim, 20 km cycle, and 5 km run). Before and during the trials, participants were randomly provided with either placebo (PLA) group, Low ED group, or High ED group. Exercise performance in the High ED group decreased significantly compared with the PLA and Low ED groups (p < 0.05). However, participants in the Low ED group also experienced an improved performance (p = 0.054). Analysis of variance revealed no differences among the three groups in cortisol and testosterone levels, or the Borg Rating of Perceived Exertion score (p > 0.5). Furthermore, superoxide dismutase (SOD) was reduced with exercise and were lowest in the High ED group. However, compared with PLA, a significant decrease of thiobarbituric acid reactive substances (TBARS) was observed in Low ED and High ED groups (p < 0.05). This indicates that caffeinated energy drink consumption may improve performance and reduce oxidative stress in sprint triathlon athletes. However, individual differences should be considered when supplementing with caffeinated energy drinks to decrease side effects.

Diagnostic and therapeutic dilemma in Stevens-Johnson syndrome-like acute graft-versus-host disease after liver transplantation: A case report.

Background: Acute graft-versus-host disease (aGVHD) is a severe and fatal complication after orthotopic liver transplantation (OLT). Clinical manifestations of severe aGVHD can resemble drug-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and there are also various medications, such as antibiotics and immunosuppressants, used after transplantation, causing a diagnostic dilemma. Furthermore, there have been no standardized diagnostic and therapeutic strategies for OLT-aGVHD due to its rarity. Case summary: A 52-year-old man presented with generalized maculopapular eruptions, fever, and pancytopenia 1 month after OLT and 4 days after taking sulfamethoxazole/trimethoprim. After assessment of the scoring criteria for drug causality of drug allergy, histopathological findings of skin biopsy, lymphocyte activation test of the potential offending drug, and microchimerism study, the diagnosis was in favor of aGVHD mimicking SJS/TEN. Considering severe sepsis, the anti-tumor necrosis factor alpha (TNF-α) agent, etanercept, was used to replace tacrolimus and corticosteroid. Skin lesions resolved gradually after anti-TNF-α biologics rescue; tacrolimus and corticosteroid therapy were re-administrated after controlling sepsis. Pancytopenia recovered and the patient was discharged in a stable condition. Conclusion: We demonstrated a diagnostic strategy for OLT-aGVHD. Targeting therapy with anti-TNF-α blockade and a temporary withdrawal of traditional immunosuppressants may be among effective and safe therapeutic options of OLT-aGVHD for those with severe sepsis.

Decreased CD11c-positive dendritic cells in the tumor microenvironment predict double-hit/triple-hit genotype and survival in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double-hit [DH] lymphoma), or fusions involving all three genes (triple-hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin-fixed paraffin-embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well-performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future.

Lessons from Acquired Natural Immunity and Clinical Trials to Inform Next-Generation Human Cytomegalovirus Vaccine Development.

Human cytomegalovirus (HCMV) infection, the most common cause of congenital disease globally, affecting an estimated 1 million newborns annually, can result in lifelong sequelae in infants, such as sensorineural hearing loss and brain damage. HCMV infection also leads to a significant disease burden in immunocompromised individuals. Hence, an effective HCMV vaccine is urgently needed to prevent infection and HCMV-associated diseases. Unfortunately, despite more than five decades of vaccine development, no successful HCMV vaccine is available. This review summarizes what we have learned from acquired natural immunity, including innate and adaptive immunity; the successes and failures of HCMV vaccine human clinical trials; the progress in related animal models; and the analysis of protective immune responses during natural infection and vaccination settings. Finally, we propose novel vaccine strategies that will harness the knowledge of protective immunity and employ new technology and vaccine concepts to inform next-generation HCMV vaccine development.