Poly(allylamine)-tripolyphosphate polymeric nanoparticle as an NLRP3-dependent systemic adjuvant for the vaccine development.

Nanotechnology plays a crucial role in vaccine development and provides the opportunity to design functional nanoparticles (Np) of different compositions, sizes, charges and surface properties for biomedical applications. The present study aims to evaluate a complex coacervate-like Np composed of poly(allylamine hydrochloride) (PAH) and tripolyphosphate (Tpp) as a safe vehicle and adjuvant for systemic vaccines. We investigated the activation of different antigen-presenting cells (APCs) with Np-PAH and its adjuvanticity in Balbc/c and different KO mice that were intraperitoneally immunized with Np-OVA. We found that Np-PAH increased the expression of CD86 and MHCII and promoted the production and secretion of interleukin-1ß (IL-1ß) and IL-18 through the inflammasome NLRP3 when macrophages and dendritic cells were co-incubated with LPS and Np-PAH. We evidenced an unconventional IL-1ß release through the autophagosome pathway. The inhibition of autophagy with 3-methyladenine reduced the LPS/Np-PAH-induced IL-1ß secretion. Additionally, our findings showed that the systemic administration of mice with Np-OVA triggered a significant induction of serum OVA-specific IgG and IgG2a, an increased secretion of IFN-γ by spleen cells, and high frequencies of LT CD4 + IFN-γ + and LT CD8 + IFN-γ + . In conclusion, our findings show that PAH-based Np promoted the inflammasome activation of innate cells with Th1-dependent adjuvant properties, making them valuable for formulating of novel preventive or therapeutic vaccines for infectious and non-infectious diseases.

Microbiome-informed study of the mechanistic basis of methane inhibition by Asparagopsis taxiformis in dairy cattle.

Copious amounts of methane, a major constituent of greenhouse gases currently driving climate change, are emitted by livestock, and efficient methods that curb such emissions are urgently needed to reduce global warming. When fed to cows, the red seaweed Asparagopsis taxiformis (AT) can reduce enteric methane emissions by up to 80%, but the achieved results can vary widely. Livestock produce methane as a byproduct of methanogenesis, which occurs during the breakdown of feed by microbes in the rumen. The ruminant microbiome is a diverse ecosystem comprising bacteria, protozoa, fungi, and archaea, and methanogenic archaea work synergistically with bacteria to produce methane. Here, we find that an effective reduction in methane emission by high-dose AT (0.5% dry matter intake) was associated with a reduction in methanol-utilizing Methanosphaera within the rumen, suggesting that they may play a greater role in methane formation than previously thought. However, a later spike in Methanosphaera suggested an acquired resistance, possibly via the reductive dehalogenation of bromoform. While we found that AT inhibition of methanogenesis indirectly impacted ruminal bacteria and fermentation pathways due to an increase in spared H2, we also found that an increase in butyrate synthesis was due to a direct effect of AT on butyrate-producing bacteria such as Butyrivibrio, Moryella, and Eubacterium. Together, our findings provide several novel insights into the impact of AT on both methane emissions and the microbiome, thereby elucidating additional pathways that may need to be targeted to maintain its inhibitory effects while preserving microbiome health and animal productivity. IMPORTANCE: Livestock emits copious quantities of methane, a major constituent of the greenhouse gases currently driving climate change. Methanogens within the bovine rumen produce methane during the breakdown of feed. While the red seaweed Asparagopsis taxiformis (AT) can significantly reduce methane emissions when fed to cows, its effects appear short-lived. This study revealed that the effective reduction of methane emissions by AT was accompanied by the near-total elimination of methane-generating Methanosphaera. However, Methanosphaera populations subsequently rebounded due to their ability to inactivate bromoform, a major inhibitor of methane formation found in AT. This study presents novel findings on the contribution of Methanosphaera to ruminal methanogenesis, the mode of action of AT, and the possibility for complementing different strategies to effectively curb methane emissions.

Assessing Executive Functioning in Schizophrenia: Concurrent and Discriminative Validity of a Novel Virtual Cooking Task.

Deficits in executive functions (EF) are strongly related to real-life functioning and negative symptoms (NS) in schizophrenia. Recently, virtual reality has enabled more ecologically valid approaches to assess EF in simulated "real-life" scenarios among which the virtual cooking task (VCT) has gained attention. However, the clinical implications of the VCT in schizophrenia have not been investigated exhaustively. In this study, clinically stable individuals with schizophrenia (n = 38) and healthy controls (n = 42) completed a novel VCT and a set of computerized standard EF tools (CST) to primarily investigate concurrent and discriminant validity. In addition, the study explored links between EF assessments, functioning, and NS while controlling for antipsychotic intake, clinical stability, and age. This VCT consisted of four tasks with increasing difficulty and time constraints. The most relevant findings indicate that (1) the VCT showed moderate to strong correlations with CST, (2) the VCT discriminated EF performance between both the groups, (3) the VCT predicted interpersonal functioning, and (4) the VCT predicted NS in greater extent than CST. Accordingly, the findings give support to the concurrent and discriminant validity of the VCT to assess EF and indicate its value to deepen the study of collateral functional deficits and NS in schizophrenia.

Bacillus Calmette-Guérin immunotherapy induces an efficient antitumor response to control murine melanoma depending on MyD88 signaling.

Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.

Dual neutrophil subsets exacerbate or suppress inflammation in tuberculosis via IL-1ß or PD-L1.

Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II-, PD-L1lo] neutrophils produced inflammasome-dependent IL-1ß in the lungs in response to virulent mycobacteria and "accelerated" deleterious inflammation, which was highly exacerbated in IFN-γR-/- mice. Regulatory [MHC-II+, PD-L1hi] neutrophils "brake" inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyperinflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1.

Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.

Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.

Silica Microparticles from Sugarcane By-Products as an Encapsulation System for Retinoids Aimed at Topical Sustained Release.

The encapsulation of retinol within silica microparticles has emerged as a promising opportunity in the realm of cosmetic and pharmaceutical formulations, driven by the need to reinforce the photoprotection and oxidation stability of retinol. This work examines the process of encapsulating retinol into silica microparticles. The association efficiency, microparticle size, molecular structure, morphology, oxidation, and release profile, as well as biocompatibility and skin sensitization, were evaluated. Results showed that 0.03% of retinol and 9% of emulsifier leads to an association efficiency higher than 99% and a particle size with an average of 5.2 µm. FTIR results indicate that there is an association of retinol with the silica microparticles, and some may be on the surface. Microscopy indicates that when association happens, there is less aggregation of the particles. Oxidation occurs in two different phases, the first related to the retinol on the surface and the second to the associated retinol. In addition, a burst release of up to 3 h (30% free retinol, 17% associated retinol) was observed, as well as a sustained release of 44% of retinol up to 24 h. Encapsulation allowed an increase in the minimal skin cytotoxic concentrations of retinol from 0.04 µg/mL to 1.25 mg/mL without skin sensitization. Overall, retinol is protected when associated with silica microparticles, being safe to use in cosmetics and dermatology.

Evaluating relugolix for the treatment of prostate cancer in real-world settings of care: the OPTYX study protocol.

OPTYX is a multi-center, prospective, observational study designed to further understand the actual experience of patients with advanced prostate cancer treated with relugolix (ORGOVYX®), an oral androgen deprivation therapy (ADT), by collecting clinical and patient-reported outcomes from routine care settings. The study aims to enroll 1000 consented patients with advanced prostate cancer from community, academic and government operated clinical practices across the USA. At planned timepoints, real-world data analysis on treatment patterns, adherence and safety as well as health outcomes and health-related quality-of-life (HRQOL) after treatment discontinuation will be published in scientific peer-reviewed journals and presented at relevant conferences. This study will provide real-world data for practitioners and researchers in their understanding of the safety and effectiveness of relugolix. Clinical Trial Registration: NCT05467176 (ClinicalTrials.gov).

What is this summary about? This is a protocol summary for a research study named OPTYX. Who can participate in this research? Men 18 or older with advanced prostate cancer initiating treatment with relugolix, an oral androgen deprivation therapy (ADT), at the time of enrollment or within the 1 month before enrollment (remaining on treatment at enrollment) and are willing and able to complete patient assessments during the study. What institutions are performing this research? Community practices, academic institutions and Veterans Health Administration facilities across the USA. What are the research assessments to obtain the results? Data will be collected from the routine medical visits twice yearly including patient demographics, medical history (co-morbidities and cardiac risk factors), prostate cancer history and treatments and test results (routine lab testosterone, PSA levels and imaging). Relugolix response and all serious adverse events (SAEs) and any nonserious adverse events (AE) leading to relugolix treatment discontinuation will be assessed. Patients will be asked to respond to evaluations about their health-related quality of life and adherence to relugolix treatment. How long would the study last? Up to 5 years from enrollment date and/or up to 2 years after relugolix discontinuation. Follow-up will end with consent withdrawal, loss to follow-up, death, or study termination, whichever comes first. What do the results of the study mean? Real-world understanding of the experience and clinical outcomes in patients with advanced prostate cancer in routine clinical care and their clinical trajectory following cessation of relugolix therapy.

Dietary Concentrate Supplementation Increases Milk Production and Reduces Predicted Greenhouse Gas Emissions Intensity in Pasture-based Commercial Dairy Farms.

Controlled studies have extensively documented that concentrate supplements typically increase enteric methane (CH4) emissions and milk yield and reduce emissions per unit of milk produced and dry matter intake. However, there have been no studies conducted to determine the effect of concentrate on predicted greenhouse gas emissions from dairy farms representing the Australian pasture-based farming system. Thus, this study sought to determine how dietary concentrate supplementation affects enteric and manure CH4, and N2O of Australian pasture-based dairy farms. The Australian Dairy Carbon Calculator was used, which incorporates emission factors and methodologies used in the National Greenhouse Gas Inventory as reported to the International Panel on Climate Change. Primary data were collected and analyzed from 120 commercial farms in Australia's major dairy regions. Then the farms were divided into 4 groups based on their dietary concentrate supplementation: ≤ 1 (low; 15 farms), 1-2 (moderate;35 farms), 2-3 (high; 35 farms), and ≥ 3 (very high; 35 farms) ton (t) of concentrate dry matter per cow per year. Sources of greenhouse gas emissions were CO2 from concentrate production, enteric CH4, and manure CH4 and N2O. Total dry matter intake, milk yield, and daily enteric CH4 production (g/day) quadratically increased with concentrate level, whereas greenhouse gas emission intensity of milk production (kg CO2eq/kg fat and protein corrected milk) decreased by 14% for farms supplementing with ≥ 3 tDM/cow per year compared with those supplementing with ≤ 1 tDM/cow per year of dietary concentrate. The emissions of N2O and CH4 from manure increased quadratically and linearly, respectively, with the increasing supplementation of concentrate. Farms supplementing 2-3 tDM/cow per year showed substantial increases in gross income, gross margin, earnings before interest and tax, and net income ($/cow/year) compared with those supplementing of ≤ 1, 1-2, and ≥ 3 tDM/cow per year. In conclusion, increasing dietary concentrate supplementation for dairy cows resulted in increased milk production per cow, reduced greenhouse gas emissions per unit of milk produced, and increased income and profit. However, a comprehensive life cycle assessment study is needed to account for carbon sequestration by other farm components such as pastures and trees, which were not considered in the present study. In addition, the present study was based on modeling and did not gather ground truth information for DMI, digestibility, crude protein, and urinary and fecal N excretion. Therefore, data should be interpreted with caution, and studies gathering such information are encouraged.

Guanylate-binding protein-5 is involved in inflammasome activation by bacterial DNA but only the cooperation of multiple GBPs accounts for control of Brucella abortus infection.

Introduction: Guanylate-binding proteins (GBPs) are produced in response to pro-inflammatory signals, mainly interferons. The most studied cluster of GBPs in mice is on chromosome 3. It comprises the genes for GBP1-to-3, GBP5 and GBP7. In humans, all GBPs are present in a single cluster on chromosome 1. Brucella abortus is a Gram-negative bacterium known to cause brucellosis, a debilitating disease that affects both humans and animals. Our group demonstrated previously that GBPs present on murine chromosome 3 (GBPchr3) is important to disrupt Brucella-containing vacuole and GBP5 itself is important to Brucella intracellular LPS recognition. In this work, we investigated further the role of GBPs during B. abortus infection. Methods and results: We observed that all GBPs from murine chromosome 3 are significantly upregulated in response to B. abortus infection in mouse bone marrow-derived macrophages. Of note, GBP5 presents the highest expression level in all time points evaluated. However, only GBPchr3-/- cells presented increased bacterial burden compared to wild-type macrophages. Brucella DNA is an important Pathogen-Associated Molecular Pattern that could be available for inflammasome activation after BCV disruption mediated by GBPs. In this regard, we observed reduced IL-1ß production in the absence of GBP2 or GBP5, as well as in GBPchr3-/- murine macrophages. Similar result was showed by THP-1 macrophages with downregulation of GBP2 and GBP5 mediated by siRNA. Furthermore, significant reduction on caspase-1 p20 levels, LDH release and Gasdermin-D conversion into its mature form (p30 N-terminal subunit) was observed only in GBPchr3-/- macrophages. In an in vivo perspective, we found that GBPchr3-/- mice had increased B. abortus burden and higher number of granulomas per area of liver tissue, indicating increased disease severity. Discussion/conclusion: Altogether, these results demonstrate that although GBP5 presents a high expression pattern and is involved in inflammasome activation by bacterial DNA in macrophages, the cooperation of multiple GBPs from murine chromosome 3 is necessary for full control of Brucella abortus infection.

Social Signal Processing in Affective Virtual Reality: Human-Shaped Agents Increase Electrodermal Activity in an Elicited Negative Environment.

Prior research on affect elicitation indicates that stimuli with social content (pictures or videos) are more arousing than nonsocial stimuli. In particular, they elicit stronger physiological arousal as measured by electrodermal activity (EDA; i.e., social EDA effect). However, it is unclear how this effect applies to virtual reality (VR), which enables an enhanced sense of presence (SoP) and ecological validity. The study here approached this question from a social-emotional VR framework. A sample of N = 72 participants (55 percent women) experienced a set of six virtual environments (VEs) in the form of emotional parks specifically designed to elicit positive, negative, or neutral affectivity. Half of these VEs included human-shaped agents (social context) and the other half omitted these agents (nonsocial context). The results supported the social EDA effect, which in addition was amplified by the reported SoP. Importantly, the VE featuring a social negative content qualified this observed social EDA effect. The finding is discussed in the light of a negativity bias reported in affect literature, through which negative stimuli typically mobilize attention and bodily activation as a mechanism linked to stress responses. The study's implications extend to the use of VR in both research and practical applications, emphasizing the role of social content in influencing affective and physiological responses.

Implications of Delayed Testosterone Recovery in Patients with Prostate Cancer.

To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer. Patient summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT.

Thermoactivated cement from construction and demolition waste for pavement base stabilization: A case study in Brazil.

Construction and demolition waste (CDW) worldwide generation accounts 10 billion tonnes yearly. The major fraction is landfilled requiring innovative recycling methods to reduce the associated environmental impacts and to increase its circularity. Our study demonstrated the feasibility of using different CDW fines to develop recycled cements and optimized the content of CDW recycled cements with well-graded crushed stone (WGCS) for use as pavement base layer. We scaled up the study obtaining CDW cement and aggregates from a local recycling plant, as well as pilot pavement sections designed, constructed and field deflections measured. As results, the CDW cement pastes exhibited accumulated heat values of up to 111 J g-1 and achieved a compressive strength of approximately 16 MPa. The unconfined compressive strength and resilient modulus (RM) achieved using CDW cement and WGCS were 2-3 and >3000 MPa, respectively. The sections constructed using CDW cement exhibited intermediate behaviour compared to those obtained using reference materials (6% Portland cement-WGCS and a conventional granular base made using WGCS). The deflection decreased over time owing to the pozzolanic reaction.

Ruminant Production from Napier Grass (Pennisetum purpureum Schum): A Review.

Napier grass (Pennisetum purpureum Schumach) supports a significant proportion of animal production in subtropical and tropical regions, but its quality is low and when offered alone, results in low ruminant production. Shifting the management of Napier grass towards a higher-quality feed increased milk yield and liveweight gain for small, mature cattle without supplementation. This review highlights the opportunity for further increases in milk and meat production for differing classes of livestock in the tropics and subtropics by improving the nutritive value of Napier grass using new best management practice flowing on to improve food security for the millions of people in these regions.

Structure and properties of Quercus robur acorn starch extracted by pulsed electric field technology.

Pulsed electric field (PEF) technology was used to extract starch from Q. robur flours using low-intensity electric fields (0 and 0.1 kV/cm) and study the impact of PEF on the structure and properties of acorn starch concerning commercial starch. PEF technology is an advantageous method for starch extraction than the aqueous steeping from an industrial perspective since reduces extraction time and allows for continuous processing of larger suspension volumes. PEF technology preserved the amylose and amylopectin contents, hydrogen bonds, and diffraction patterns, as well as the starch native properties. Hence, PEF could be used to obtain native starches, but future studies should verify its economic viability. Acorn starches have lower damaged starch content, gelatinization temperatures, enthalpies, improved pseudoplastic behavior, reduced in-vitro digestibility, and lower resistance to deformation compared to commercial corn starch. The higher solubility and swelling power of acorn starches up to 80 °C make them a suitable food additive in fermented yogurt and milk products and thus help to value acorn and acorn starches. Hence, acorns can be used to obtain native starches, a food ingredient with a wide range of food and non-food usage, using PEF.

A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.

Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (-)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1's tert-butyl moiety as a PXR anchor and explains binding by (-)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (-)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes.

The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections.

The bacillus Calmette-Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines.

Napier grass (Pennisetum purpureum Schum) management strategies for dairy and meat production in the tropics and subtropics: yield and nutritive value.

Napier grass (Pennisetum purpureum Schumach) comprises up to 80% of the cattle diet in many tropical and subtropical regions and is used primarily by smallholder farmers. Despite the grass's high yield, resulting animal productivity from this grass is low. One of the key reasons for the low animal productivity of Napier grass is its low nutritive value under current management. Taken together, previous work has shown the current yield, crude protein (CP), and metabolisable energy (ME) of Napier grass to be 26 t dry matter (DM)/ha/year, 96 g/kg DM, and 8.7 MJ/kg DM, respectively, ranging from 2 to 86 t DM/ha/year, 9 to 257 g CP/kg DM, and 5.9 to 10.8 MJ ME/kg DM, respectively, suggesting an opportunity for significant improvement on both yield and nutritive value of this grass. The DM yield and nutritive value of this grass are inversely related, indicating a trade-off between yield and quality; however, this trade-off could be minimised by increasing sowing density and harvesting frequency. Available literature shows that this simple management strategy of increasing sowing density (50 cm × 40 cm) and harvesting frequency (11-12 harvests/year) provides 71 t DM/ha with 135 g/kg DM CP and 10.8 MJ ME/kg DM. This quality of Napier grass has the potential to increase both milk and meat production substantially in the tropics and subtropics, and the farmers will likely find this simple management acceptable due to the high yield obtained through this management. However, there is a paucity of work in this field. Therefore, management strategies to improve the nutritive value of Napier grass are required to increase milk and meat production in the tropics and subtropics and in doing so improve the food security of more than half of the global population living in these regions.

Amyand's hernia in a patient with acute complicated diverticulitis. A case report and review of the literature.

INTRODUCTION: Amyand's hernia with an inflamed or perforated appendix is rare with incidence of 0.1 % and 0.01 % of cases respectively. It has been described in conjunction with cecal perforation, cholecystitis and ureterolithiasis. Yet, its association with acute sigmoid diverticulitis has never been reported before. PRESENTATION OF CASE: A 57-year-old male presented to the emergency department with acute abdomen and an indurated right inguinal mass. A preoperative computed tomography (CT) scan reported a giant inflamed sigmoid diverticulum and an Amyand's hernia with a complicated appendicitis. The patient was taken to the operating room and a midline laparotomy incision was made. A giant sigmoid diverticulum with ischemic patches was encountered. The cecal appendix was found inside the right inguinal canal, with a perforation in its distal third. A Hartmann's procedure, appendicectomy and non-mesh inguinal hernia repair was accomplished. DISCUSSION: Case reports of Amyand's hernia in patients with simultaneous abdominal conditions are scarce. Symptoms in these patients could be various and may lead to preoperative imaging and diagnosis. In this case acute abdomen in physical examination demanded imaging analysis and a preoperative diagnosis of acute diverticulitis and Amyand's hernia with a perforated appendicitis was made. CONCLUSIONS: Amyand's hernia with acute perforated appendicitis is a rare entity. CT scan is useful for diagnosis of Amyand's hernia and associated conditions. Preoperative diagnosis of Amyand's hernia and concomitant abdominal disease aids in the therapeutic approach and management. To our knowledge this is the first case report of an Amyand's hernia in a patient with acute diverticulitis.