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Tuberculosis in patients with systemic lupus erythematosus
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tb), with approximately 10 million new cases reported worldwide annually. Patients with immunocompromised states or those receiving immunosuppressive therapy for autoimmune diseases are at higher risk of M. tb infection or reactivation. The chronic autoimmune disease, systemic lupus erythematosus (SLE), is associated with a higher risk of M. tb infection and TB disease during conventional treatment with corticosteroids and immunosuppressants. However, whether risk of TB is influenced by the immune disturbances associated with active SLE when patients are not receiving immunosuppressant treatment remains unclear. In this review, we describe the pathogenesis of TB and SLE and consider how autoimmune responses in SLE could influence TB risk.
New Vaccine Strategies to Improve, Boost, or Replace BCG
Over a century after it was first introduced, the live attenuated vaccine Bacille Calmette-Guérin (BCG) remains the only licenced vaccine against tuberculosis (TB). BCG is currently administered to more than 100 million children worldwide every year, yet the precise degree to which it protects against TB and the immune mechanisms underlying such protection remain unclear. While BCG is effective in some populations some of the time, overall, it has failed to control the global TB epidemic, and a more effective vaccine strategy is urgently needed. There are several viable pathways to a more effective TB vaccine represented in the current preclinical and clinical pipelines. These include improvements to BCG itself using genetic modifications to generate recombinant strains, administering BCG by different routes, or revaccination regimens that prolong the protective effects of BCG further into adolescence or adulthood. Alternatively, BCG may be boosted with heterologous subunit vaccines or be replaced altogether with live attenuated/inactivated strains of other mycobacteria or with DNA or RNA vaccines. In this chapter, we discuss each of these approaches and summarize current data on novel TB vaccines that aim to improve, boost, or replace BCG with a focus on the most promising candidates in preclinical development.
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines.
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines.
Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA-lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2-specific T cells and inform the optimization of mRNA vaccination regimens.
Diagnostic ultrasound to inform the surgical approach to cesarean delivery in patients at high risk for placenta accreta spectrum disorders.
BACKGROUND: Uterine sparing surgery has become an option for patients with placenta accreta spectrum disorders. The decision to perform a cesarean hysterectomy versus uterine sparing surgery is made intraoperatively. This study was undertaken to assess the value of ultrasound markers in predicting hysterectomy. OBJECTIVE: To describe ultrasound markers associated with the need for cesarean hysterectomy in patients at risk of placenta accreta spectrum. STUDY DESIGN: This was an analysis of a prospectively collected data of high risk placenta accreta spectrum patients between September 2023 and August 2024. Ultrasound examination was performed by an expert focusing on the diagnosis of placenta accreta spectrum. All patients were counselled regarding the management options available at our center, namely uterine-sparing surgery and hysterectomy. All patients opted for a uterine sparing surgery if safe and technically feasible. The final choice of surgical management approach was solely based on the intraoperative topography which describes the size and location of the abnormally adhered placenta. The primary outcome was the need for hysterectomy despite a preoperative plan for uterine-sparing surgery. RESULTS: A total of 123 participants were enrolled: 93 placenta accreta spectrum cases and 30 non-placenta accreta scar dehiscence cases. Uterine sparing surgery was successful in 74 out of 93(79.6%) placenta accreta spectrum cases and 100% non-placenta accreta scar dehiscence cases. Least Absolute Shrinkage and Selection Operator penalised regression revealed intracervical hypervascularity >50%, distorted urinary bladder wall, and parametrial hypervascularity as the most influential predictors for hysterectomy. This best-fitted model achieved accuracy of 94% (95% CI: 81.3% - 99.3%) after model cross-validation. The combination of intracervical hypervascularity >50% and distorted bladder wall had the highest predictive probability for hysterectomy, with a value of 0.87 (95% CI: 0.81 - 0.93), sensitivity of 96.0% (95% CI 89.0 - 99.0%) and specificity of 92.0%(95% CI 62.0 - 100.0). CONCLUSION: Comprehensive preoperative ultrasound can reasonably predict the appropriate surgical approach to placenta accreta spectrum. This can be achieved by assessing intracervical hypervascularity and a distorted urinary bladder wall using a combination of transabdominal, transvaginal, and color Doppler ultrasound techniques, as these signs have a strong correlation with the need for hysterectomy in a cohort where the intention to treat was uterine sparing surgery.
Human tonsil organoids reveal innate pathways modulating humoral and cellular responses to ChAdOx1.
The COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19. Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN-ɑ was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN-⍺-dependent and independent manners, indicating intricate signaling interplay. IFN-ɑ and IL-6 also regulated the function of vaccine-activated CD4+ T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies.
Estimates of HIV-1 within-host recombination rates across the whole genome.
Recombination plays a pivotal role in generating within-host diversity and enabling HIV's evolutionary success, particularly in evading the host immune response. Despite this, the variability in recombination rates across different settings and the underlying factors that drive these differences remain poorly understood. In this study, we analysed a large dataset encompassing hundreds of untreated, longitudinally sampled infections using both whole-genome long-read and short-read sequencing datasets. By quantifying recombination rates, we uncover substantial variation across subtypes, viral loads, and stages of infection. We also map recombination hot and cold spots across the genome using a sliding window approach, finding that previously reported inter-subtype regions of high or low recombination are replicated at the within-host level. Importantly, our findings reveal the significant influence of selection on recombination, showing that the presence and success of recombinant genomes is strongly interconnected with the fitness landscape. These results offer valuable insights into the contribution of recombination to evolutionary dynamics and demonstrate the enhanced resolution that long-read sequencing offers for studying viral evolution.
Is health, growth and development impaired in children who are Hepatitis B-exposed but uninfected?
An estimated 254 million people are living with chronic hepatitis B virus (HBV) infection worldwide. Many infants are born to mothers with HBV but do not themselves acquire the infection. It is unclear whether this exposure to HBV in early life - without the development of active infection - may be associated with adverse outcomes. We propose the term "HBV-exposed uninfected (HBEU)", drawing parallels with the HIV field which recognises that children who are HIV-exposed but uninfected face an increased risk of adverse health outcomes. This paper explores the potential health consequences for children HBEU. We summarise existing evidence reporting on children HBEU, and also review existing knowledge from the HIV field that could inform insights. We hypothesise that children HBEU may be at increased risk of preterm birth, and/or impaired growth and neurodevelopmental delay, but comprehensive, longitudinal studies are currently lacking to support this. We propose a conceptual framework to hypothesise how exposure to HBV could potentially lead to adverse growth and neurodevelopment through both HBV-specific and universal pathways, and review the available evidence and research gaps. Data are needed to establish whether short- and long-term sequelae exist for children HBEU, and to inform evidence-based interventions to mitigate against detrimental outcomes. Establishing a comprehensive understanding of the long-term trajectory of health and well-being among children HBEU throughout childhood into adolescence will require longitudinal observational studies with appropriate control groups to characterise outcomes, identify risk factors and explore underlying mechanistic pathways.
Chicken TCRγδ+CD8α+T cells are antigen-specific and protective in H9N2 AIV infection.
TCRγδ+ T cells are a major lymphocyte population of chickens, but their response or contribution to immunity against avian influenza virus (AIV) remains unknown. Here, we report an increase in the proportion and activation state of TCRγδ+CD8α+ T cells in the PBMCs of 3 chicken lines (MHC homozygous H-B2 and H-B21 lines and outbred G-WL line) with the strongest responses observed in the more resistant H-B2 chickens. H9N2 AIV infection induced mRNA upregulation of interferon (IFN)-γ and cytotoxicity-associated molecules, including, Granzyme A, Granzyme K, and perforin in sorted TCRγδ+CD8α+ T cells. Moreover, in ex vivo cultured TCRγδ+CD8α+ T cells in response to H9N2 AIV infected splenocytes, strongly indicates the activation of these cells' cytolytic potential via detection of transcription levels of cytotoxic genes with quantitative reverse transcription polymerase chain reaction (qRT-PCR), and IFN-γ protein level with ELISPOT and an intracellular cytokine staining assays. Most importantly, in vivo depletion of γδ T cells led to reduced H9N2 AIV control, which was particularly evident in the early phase of infection. Taken together, these results indicate that strong TCRγδ+CD8α+T cell response plays a critical role in protecting chicken against H9N2 AIV infection.
Hypothetical performance of syndrome-based management of acute paediatric admissions of children aged more than 60 days in a Kenyan district hospital
OBJECTIVE: To investigate whether the outpatient, syndrome-based approach of the Integrated Management of Childhood Illness (IMCI) protocol could be extended to the inpatient arena to give clear and simple minimum standards of care for poorly resourced facilities. METHODS: A prospective, one-year admission cohort retrospectively compared hypothetical performance of syndrome-based management with paediatrician-defined final diagnosis. Admission syndrome definitions were based on local adaptations to the IMCI protocol that encompassed 20 clinical features, measurement of oxygen saturation, and malaria microscopy. FINDINGS: After 315 children with clinically obvious diagnoses (e.g. sickle cell disease and burns) were excluded, 3705 admission episodes were studied. Of these, 2334 (63%) met criteria for at least one severe syndrome (mortality 8% vs <1% for "non-severe" cases), and half of these had features of two or more severe syndromes. No cases of measles were seen. Syndrome-based treatment would have been appropriate (sensitivity >95%) for severe pneumonia, severe malaria, and diarrhoea with severe dehydration, and probably for severe malnutrition (sensitivity 71%). Syndrome-directed treatment suggested the use of broad-spectrum antibiotics in 75/133 (56% sensitivity) children with bacteraemic and 63/71 (89% sensitivity) children with meningitis. CONCLUSIONS: Twenty clinical features, oxygen saturation measurements, and results of malaria blood slides could be used for inpatient, syndrome-based management of acute paediatric admissions. The addition of microscopy of the cerebrospinal fluid and haemoglobin measurements would improve syndrome-directed treatment considerably. This approach might rationalize admission policy and standardize inpatient paediatric care in resource-poor countries, although the clinical detection of bacteraemia remains a problem.
Clarifying the taxonomy of the Finch Louse Fly Ornithomya fringillina (Curtis) (Diptera: Hippoboscidae) – an analysis of morphotypes
The louse flies in the genus Ornithomya are avian ectoparasites. The patterns of alar microtrichia on the wings of the Ornithomyae are commonly used to help distinguish the various species, with the patterns in most species found to be constant between individuals. The Finch Louse Fly Ornithomya fringillina (Curtis) in the United Kingdom, Ireland and the Isle of Man, is unusual in that the several patterns have been described. Consequently it has a complicated taxonomic history and there is some confusion about species identification. Louse flies were collected by licensed bird ringers and an analysis of the simple morphological features, phenology and geographical distribution of these traits was performed. No significant differences were found between the three main types, and it was concluded that the differences were not due to sexual dimorphism and did not provide evidence that the different forms were separate species. Analysis of COX1 DNA sequences confirmed this result and proved that these are indeed morphotypes and not distinct species. There was no geographical separation between COX1 sequences from the United Kingdom and those from flies sampled in other parts of the world. The molecular analysis also suggested that Ornithomya bequaerti (Maa) and Ornithomya candida (Maa) may not be valid species, but represent morphotypes of O. fringillina.
An artificial intelligence-based approach to identify volume status in patients with severe dengue using wearable PPG data.
Dengue shock syndrome (DSS) is a serious complication of dengue infection which occurs when critical plasma leakage results in haemodynamic shock. Treatment is challenging as fluid therapy must balance the risk of hypoperfusion with volume overload. In this study, we investigate the potential utility of wearable photoplethysmography (PPG) to determine volume status in DSS. In this prospective observational study, we enrolled 250 adults and children with a clinical diagnosis of dengue admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. PPG monitoring using a wearable device was applied for a 24-hour period. Clinical events were then matched to the PPG data by date and time. We predefined two clinical states for comparison: (1) the 2-hour period before a shock event was an "empty" volume state and (2) the 2-hour period between 1 and 3 hours after a fluid initiation event was a "full" volume state. PPG data were sampled from these states for analysis. Variability and waveform morphology features were extracted and analyzed using principal components analysis and random forest. Waveform images were used to develop a computer vision model. Of the 250 patients enrolled, 90 patients experienced the predefined outcomes, and had sufficient data for the analysis. Principal components analysis identified four principal components (PCs), from the 23 pulse wave features. Logistic regression using these PCs showed that the empty state is associated with PCs 1 (p = 0.016) and 4 (p = 0.036) with both PCs denoting increased sympathetic activity. Random forest showed that heart rate and the LF-HF ratio are the most important features. A computer vision model had a sensitivity of 0.81 and a specificity of 0.70 for the empty state. These results provide proof of concept that an artificial intelligence-based approach using continuous PPG monitoring can provide information on volume states in DSS.