Location versus ID: what matters to lung-resident memory T cells?

Tissue-resident memory T cells (TRM cells) are vital for the promotion of barrier immunity. The lung, a tissue constantly exposed to foreign pathogenic or non-pathogenic antigens, is not devoid of these cells. Lung TRM cells have been considered major players in either the protection against respiratory viral infections or the pathogenesis of lung allergies. Establishment of lung TRM cells rely on intrinsic and extrinsic factors. Among the extrinsic regulators of lung TRM cells, the magnitude of the impact of factors such as the route of antigen entry or the antigen natural tropism for the lung is not entirely clear. In this perspective, we provide a summary of the literature covering this subject and present some preliminary results on this potential dichotomy between antigen location versus antigen type. Finally, we propose a hypothesis to synthesize the potential contributions of these two variables for lung TRM cell development.

Photobiomodulation Therapy to Treat Snakebites Caused by Bothrops atrox: A Randomized Clinical Trial.

Importance: Bothrops venom acts almost immediately at the bite site and causes tissue damage. Objective: To investigate the feasibility and explore the safety and efficacy of low-level laser therapy (LLLT) in reducing the local manifestations of B atrox envenomations. Design, Setting, and Participants: This was a double-blind randomized clinical trial conducted at Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, in Manaus, Brazil. A total of 60 adult participants were included from November 2020 to March 2022, with 30 in each group. Baseline characteristics on admission were similarly distributed between groups. Data analysis was performed from August to December 2022. Intervention: The intervention group received LLLT combined with regular antivenom treatment. The laser used was a gallium arsenide laser with 4 infrared laser emitters and 4 red laser emitters, 4 J/cm2 for 40 seconds at each application point. Main Outcomes and Measures: Feasibility was assessed by eligibility, recruitment, and retention rates; protocol fidelity; and patients' acceptability. The primary efficacy outcome of this study was myolysis estimated by the value of creatine kinase (U/L) on the third day of follow-up. Secondary efficacy outcomes were (1) pain intensity, (2) circumference measurement ratio, (3) extent of edema, (4) difference between the bite site temperature and that of the contralateral limb, (5) need for the use of analgesics, (6) frequency of secondary infections, and (7) necrosis. These outcomes were measured 48 hours after admission. Disability assessment was carried out from 4 to 6 months after patients' discharge. P values for outcomes were adjusted with Bonferroni correction. Results: A total of 60 patients (mean [SD] age, 43.2 [15.3] years; 8 female individuals [13%] and 52 male individuals [87%]) were included. The study was feasible, and patient retention and acceptability were high. Creatine kinase was significantly lower in the LLLT group (mean [SD], 163.7 [160.0] U/L) 48 hours after admission in relation to the comparator (412.4 [441.3] U/L) (P = .03). Mean (SD) pain intensity (2.9 [2.7] vs 5.0 [2.4]; P = .004), circumference measurement ratio (6.6% [6.6%] vs 17.1% [11.6%]; P < .001), and edema extent (25.8 [15.0] vs 40.1 [22.7] cm; P = .002) were significantly lower in the LLLT group in relation to the comparator. No difference was observed between the groups regarding the mean difference between the bite site temperature and the contralateral limb. Secondary infections, necrosis, disability outcomes, and the frequency of need for analgesics were similar in both groups. No adverse event was observed. Conclusions and Relevance: The data from this randomized clinical trial suggest that the use of LLLT was feasible and safe in a hospital setting and effective in reducing muscle damage and the local inflammatory process caused by B atrox envenomations. Trial Registration: Brazilian Registry of Clinical Trials Identifier: RBR-4qw4vf.

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections.

CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observe that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3, favoring parenchymal CD4+ T cell accumulation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections.

Prospecting Local Treatments Used in Conjunction with Antivenom Administration Following Envenomation Caused by Animals: A Systematic Review.

Envenomation caused by venomous animals may trigger significant local complications such as pain, edema, localized hemorrhage, and tissue necrosis, in addition to complications such as dermonecrosis, myonecrosis, and even amputations. This systematic review aims to evaluate scientific evidence on therapies used to target local effects caused by envenomation. The PubMed, MEDLINE, and LILACS databases were used to perform a literature search on the topic. The review was based on studies that cited procedures performed on local injuries following envenomation with the aim of being an adjuvant therapeutic strategy. The literature regarding local treatments used following envenomation reports the use of several alternative methods and/or therapies. The venomous animals found in the search were snakes (82.05%), insects (2.56%), spiders (2.56%), scorpions (2.56%), and others (jellyfish, centipede, sea urchin-10.26%). In regard to the treatments, the use of tourniquets, corticosteroids, antihistamines, and cryotherapy is questionable, as well as the use of plants and oils. Low-intensity lasers stand out as a possible therapeutic tool for these injuries. Local complications can progress to serious conditions and may result in physical disabilities and sequelae. This study compiled information on adjuvant therapeutic measures and underscores the importance of more robust scientific evidence for recommendations that act on local effects together with the antivenom.

Pannexin-1 channels promote CD8+ T cell effector and memory responses through distinct intracellular pathways.

Sensing of extracellular metabolites controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses to antigen, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 favors memory CD8+ T cell survival primarily through ATP export and induction of mitochondrial metabolism. CD8-specific Panx1 is also crucial for the effector expansion of CD8+ T cells, however this regulation occurs independently of eATP. Instead, our results suggest a connection between Panx1-induced extracellular lactate accumulation and the complete activation of effector CD8+ T cells. In summary, Panx1 regulates effector and memory CD8+ T cells through export of distinct metabolites and by engaging different metabolic and signaling pathways.

The effect of BCG vaccination on infection and antibody levels against SARS-CoV-2-The results of ProBCG: a multicenter randomized clinical trial in Brazil.

OBJECTIVES: Evatuate if Bacillus Calmette-Guérin (BCG) vaccine could be used as a tool against SARS-CoV-2 based on the concept of trained immunity. METHODS: A multicenter, double-blinded, randomized clinical trial recruited health care workers (HCWs) in Brazil. The incidence rates of COVID-19, clinical manifestations, absenteeism, and adverse events among HCWs receiving BCG vaccine (Moreau or Moscow strains) or placebo were compared. BCG vaccine-mediated immune response before and after implementing specific vaccines for COVID-19 (CoronaVac or COVISHIELD) was analyzed. Cox proportional hazard and linear mixed effect modeling were used. RESULTS: A total of 264 volunteers were included for analysis (BCG = 134 and placebo = 130). The placebo group presented a COVID-19 cumulative incidence of 0.75% vs 0.52% of BCG. The Moreau strain also presented a higher incidence rate (1.60% × 0.22%). BCG did not show a protective hazard ratio against COVID-19. In addition, the log (immunoglobulin G) level against SARS-CoV-2 presented a higher increase in the BCG group, whether or not participants had COVID-19, but also without statistical significance. CONCLUSION: Our results suggest that BCG has a tendency of protection against SARS-CoV-2 and higher immunoglobulin G levels than placebo. The clinical trial was registered at https://clinicaltrials.gov/ (NCT04659941).

P2RX7 Enhances Tumor Control by CD8+ T Cells in Adoptive Cell Therapy.

Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes the generation of memory populations following acute infections. However, data suggest that P2RX7 may limit the efficacy of antitumor responses. Herein, we show that P2RX7 is beneficial for optimal melanoma control in a mouse CD8+ T-cell adoptive transfer model. Tumor-specific P2rx7-/- CD8+ T cells exhibited impaired mitochondrial maintenance and function but did not display signs of overt exhaustion early in the antitumor response. However, as the tumor burden increased, the relative frequency of P2RX7-deficient CD8+ T cells declined within the tumor; this correlated with reduced proliferation, increased apoptosis, and mitochondrial dysfunction. Extending these studies, we found that the transient in vitro stimulation of P2RX7 using the ATP analogue BzATP led to enhanced B16 melanoma control by CD8+ T cells. These findings are in keeping with the concept that extracellular ATP (eATP) sensing by P2RX7 on CD8+ T cells is required for their ability to efficiently eliminate tumors by promoting mitochondrial fitness and underscore the potential for P2RX7 stimulation as a novel therapeutic treatment to enhance tumor immunotherapy.

68Ga-Prostate-specific membrane antigen (PSMA) positron emission tomography (pet) in prostate cancer: a systematic review and meta-analysis

ABSTRACT Introduction: Prostate cancer (PC) is the second most commonly diagnosed cancer in males. 68Ga-PSMA PET/CT, a non-invasive diagnostic tool to evaluate PC with prostate-specific membrane antigen (PSMA) expression, has emerged as a more accurate alternative to assess disease staging. We aimed to identify predictors of positive 68Ga-PSMA PET and the accuracy of this technique. Materials and methods: Diagnostic accuracy cross-sectional study with prospective and retrospective approaches. We performed a comprehensive literature search on PubMed, Cochrane Library, and Embase database in search of studies including PC patients submitted to radical prostatectomy or radiotherapy with curative intent and presented biochemical recurrence following ASTRO 1996 criteria. A total of 35 studies involving 3910 patients submitted to 68-Ga-PSMA PET were included and independently assessed by two authors: 8 studies on diagnosis, four on staging, and 23 studies on restaging purposes. The significance level was α=0.05. Results: pooled sensitivity and specificity were 0.90 (0.86-0.93) and 0.90 (0.82-0.96), respectively, for diagnostic purposes; as for staging, pooled sensitivity and specificity were 0.93 (0.86-0.98) and 0.96 (0.92-0.99), respectively. In the restaging scenario, pooled sensitivity and specificity were 0.76 (0.74-0.78) and 0.45 (0.27-0.58), respectively, considering the identification of prostate cancer in each described situation. We also obtained specificity and sensitivity results for PSA subdivisions. Conclusion: 68Ga-PSMA PET provides higher sensitivity and specificity than traditional imaging for prostate cancer.

Influência de substâncias irrigadoras endodônticas na microdureza da dentina radicular: revisão integrativa / Influence of endodontic irrigation substances on the microdurity of the radicular dentin: integrative review

As soluções de irrigação são essenciais como auxiliares na limpeza e desinfecção do sistema de canais radiculares (SCR). Entretanto, essas substâncias químicas podem gerar alterações na composição da dentina. Assim, o presente estudo teve como objetivo avaliar, por meio de uma revisão integrativa, os efeitos do hipoclorito de sódio (NaOCl) a 1%; 2,5%; 3%; 5%; 5,25%; 6% e 17%; digluconato de clorexidina (CHX) a 2% e EDTA 2,5%; 5%; 15% e 17% sobre a microdureza da dentina do canal radicular após sua utilização como solução irrigadora. Foi realizada uma revisão integrativa nas bases de dados: PubMed, Cochrane e Lilacs, utilizando-se os seguintes descritores em inglês: "irrigating solutions"; "chelaling agentes"; "dentin microhardness"; "EDTA"; "sodium hypochlorite"; "chlorhexidine gluconate". Foi utilizado o conector "and" associando dentin microhardness aos outros descritores. Critérios de inclusão: Artigos científicos na área da odontologia, escritos em inglês e português que aborda o tema "As soluções de hipoclorito de sódio (NaOCl), digluconato de clorexidina (CHX) e EDTA influenciam na microdureza da dentina radicular?''. Critérios de exclusão: artigos repetidos em mais de uma base de dados, livros, teses de doutorado, dissertações de mestrado, resumos e trabalhos publicados em congresso. Fortes evidências indicam que o hipoclorito de sódio, digluconato de clorexidina e EDTA influenciam na microdureza da dentina radicular, quando utilizadas como solução irrigadora durante o tratamento endodôntico... (AU)

Irrigation solutions are essential as an aid in cleaning and disinfecting the root canal system (SCR). However, these chemicals can cause changes in the composition of dentin. Thus, the present study aimed to evaluate, through an integrative review, the effects of 1% sodium hypochlorite (NaOCl); 2.5%; 3%; 5%; 5.25%; 6% and 17%; 2% chlorhexidine digluconate (CHX) and 2.5% EDTA; 5%; 15% and 17% on the microhardness of root canal dentin after its use as an irrigating solution. An integrative review was carried out in the databases: PubMed, Cochrane and Lilacs, using the following descriptors in English: "irrigating solutions"; "chelaling agents"; "dentin microhardness"; "EDTA"; "sodium hypochlorite"; "chlorhexidine gluconate". The "and" connector was used, associating dentin microhardness with other descriptors. Inclusion criteria: Scientific articles in the field of dentistry, written in English and Portuguese that address the topic "Do solutions of sodium hypochlorite (NaOCl), chlorhexidine gluconate (CHX) and EDTA influence the microhardness of root dentin?". Exclusion criteria: articles repeated in more than one database, books, doctoral theses, master's dissertations, abstracts and papers published in congress. Strong evidence indicates that sodium hypochlorite, chlorhexidine gluconate and EDTA influence the microhardness of root dentin when used as an irrigating solution during endodontic treatment... (AU)

68Ga-Prostate-specific membrane antigen (psma) positron emission tomography (pet) in prostate cancer: a systematic review and meta-analysis.

INTRODUCTION: Prostate cancer (PC) is the second most commonly diagnosed cancer in males. 68Ga-PSMA PET/CT, a non-invasive diagnostic tool to evaluate PC with prostate-specific membrane antigen (PSMA) expression, has emerged as a more accurate alternative to assess disease staging. We aimed to identify predictors of positive 68Ga-PSMA PET and the accuracy of this technique. MATERIALS AND METHODS: Diagnostic accuracy cross-sectional study with prospective and retrospective approaches. We performed a comprehensive literature search on PubMed, Cochrane Library, and Embase database in search of studies including PC patients submitted to radical prostatectomy or radiotherapy with curative intent and presented biochemical recurrence following ASTRO 1996 criteria. A total of 35 studies involving 3910 patients submitted to 68-Ga-PSMA PET were included and independently assessed by two authors: 8 studies on diagnosis, four on staging, and 23 studies on restaging purposes. The significance level was α=0.05. RESULTS: pooled sensitivity and specificity were 0.90 (0.86-0.93) and 0.90 (0.82-0.96), respectively, for diagnostic purposes; as for staging, pooled sensitivity and specificity were 0.93 (0.86-0.98) and 0.96 (0.92-0.99), respectively. In the restaging scenario, pooled sensitivity and specificity were 0.76 (0.74-0.78) and 0.45 (0.27-0.58), respectively, considering the identification of prostate cancer in each described situation. We also obtained specificity and sensitivity results for PSA subdivisions. CONCLUSION: 68Ga-PSMA PET provides higher sensitivity and specificity than traditional imaging for prostate cancer.

Avaliação dos profissionais de saúde no atendimento antirrábico humano / Evaluation of health professionals in human antirrabic care

Objetivo: avaliar a conduta dos profissionais de saúde no atendimento antirrábico humano. Método: estudo quantitativo, descritivo, com 2.789 casos que sofreram agressão por cão ou gato para a profilaxia antirrábica humana pós-exposição, no período de 2013 a 2015, notificados no Sinan. Os dados foram analisados pelo programa Stata 12.0 e realizou-se análise de regressão logística para a avaliação da adequação da conduta. Resultados: a mordedura representou maior proporção dos casos (85,6%). Os cães e gatos representaram 98,4% das espécies agressoras. Desses, 81,8% foram referidos como sadios. Dos tratamentos indicados, 68% foram do tipo observação e vacina. Constatou-se que, das condutas indicadas, 70,1% foram adequadas. Conclusão: a partir da avaliação das condutas dos profissionais de saúde no atendimento antirrábico humano, pôde-se verificar que a maioria delas foi realizada da forma correta e de acordo com as normas ministeriais. No entanto, constatou-se um número considerável de condutas inadequadas refletindo a necessidade constante de qualificação dos profissionais para a instituição da profilaxia antirrábica.(AU)

Can positron emission mammography help to identify clinically significant breast cancer in women with suspicious calcifications on mammography?

OBJECTIVE: To evaluate the diagnostic accuracy of positron emission mammography (PEM) for identifying malignant lesions in patients with suspicious microcalcifications detected on mammography. METHODS: A prospective, single-centre study that evaluated 40 patients with suspicious calcifications at mammography and indication for percutaneous or surgical biopsy, with mean age of 56.4 years (range: 28-81 years). Patients who agreed to participate in the study underwent PEM with 18F-fluorodeoxyglucose before the final histological evaluation. PEM findings were compared with mammography and histological findings. RESULTS: Most calcifications (n = 34; 85.0 %) were classified as BIRADS 4. On histology, there were 25 (62.5 %) benign and 15 (37.5 %) malignant lesions, including 11 (27.5 %) ductal carcinoma in situ (DCIS) and 4 (10 %) invasive carcinomas. On subjective analysis, PEM was positive in 15 cases (37.5 %) and most of these cases (n = 14; 93.3 %) were confirmed as malignant on histology. There was one false-positive result, which corresponded to a fibroadenoma, and one false negative, which corresponded to an intermediate-grade DCIS. PEM had a sensitivity of 93.3 %, specificity of 96.0 % and accuracy of 95 %. CONCLUSION: PEM was able to identify all invasive carcinomas and high-grade DCIS (nuclear grade 3) in the presented sample, suggesting that this method may be useful for further evaluation of patients with suspected microcalcifications. KEY POINTS: • Many patients with suspicious microcalcifications at mammography have benign results at biopsy. • PEM may help to identify invasive carcinomas and high-grade DCIS. • Management of patients with suspicious calcifications can be improved.