The Endogenous Retinoic Acid Receptor Pathway Is Exploited by Mycobacterium tuberculosis during Infection, Both In Vitro and In Vivo.

Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies.

Recombinant Bacillus Calmette-Guérin Expressing SARS-CoV-2 Chimeric Protein Protects K18-hACE2 Mice against Viral Challenge.

COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development. We investigated whether rBCG-ChD6 immunization followed by a boost with the recombinant nucleocapsid and spike chimera (rChimera), together with alum, provided protection against SARS-CoV-2 infection in K18-hACE2 mice. A single dose of rBCG-ChD6 boosted with rChimera associated with alum elicited the highest anti-Chimera total IgG and IgG2c Ab titers with neutralizing activity against SARS-CoV-2 Wuhan strain when compared with control groups. Importantly, following SARS-CoV-2 challenge, this vaccination regimen induced IFN-γ and IL-6 production in spleen cells and reduced viral load in the lungs. In addition, no viable virus was detected in mice immunized with rBCG-ChD6 boosted with rChimera, which was associated with decreased lung pathology when compared with BCG WT-rChimera/alum or rChimera/alum control groups. Overall, our study demonstrates the potential of a prime-boost immunization system based on an rBCG expressing a chimeric protein derived from SARS-CoV-2 to protect mice against viral challenge.

Use of a Paclitaxel Drug-Eluting Stent for the Treatment of Hemodialysis Access Outflow Stenosis.

PURPOSE: To evaluate the outcomes and durability of drug-eluting stents (DESs) for the treatment of hemodialysis access outflow stenosis. MATERIAL AND METHODS: A single-center retrospective analysis was conducted of all patients with hemodialysis vascular access outflow stenosis treated with a paclitaxel-coated DES (Eluvia; Boston Scientific, Marlborough, Massachusetts) between January 2020 and July 2022. A total of 34 DESs were implanted to treat outflow stenosis in 32 patients. Primary target lesion patency after stent deployment was the main outcome. Comparison between the time interval free from target lesion reintervention (TLR) after previous plain balloon angioplasty (PBA) and that after stent deployment for the same target lesion was considered a secondary outcome. RESULTS: The primary patency at 6, 12, and 18 months was 63.1%, 47.6%, and 41.7%, respectively. The secondary patency rate was 100% at 18 months. The median time interval free from TLR increased from 4.1 to 11.9 months (P < .001). No adverse events were observed during the median follow-up period of 387 days. CONCLUSIONS: The patency rates after use of DES for hemodialysis access outflow stenosis were comparable with results for drug-coated balloons and stent grafts, addressing recoil and minimizing the risk of jailing by a covered stent.

Clinical, immunological, and microbiological analysis of the association between periodontitis and COVID-19: a case-control study.

PURPOSE: Periodontitis and coronavirus disease (COVID-19) share risk factors and activate similar immunopathological pathways, intensifying systemic inflammation. This study investigated the clinical, immunological and microbiological parameters in individuals with COVID-19 and controls, exploring whether periodontitis-driven inflammation contributes to worsening COVID-19 endpoints. METHODS: Case (positive RT-PCR for SARS-CoV-2) and control (negative RT-PCR) individuals underwent clinical and periodontal assessments. Salivary levels of TNF-α, IL-6, IL-1ß, IL-10, OPG, RANKL, neutrophil extracellular traps, and subgingival biofilm were analyzed at two timepoints. Data on COVID-19-related outcomes and comorbidity information were evaluated from medical records. RESULTS: Ninety-nine cases of COVID-19 and 182 controls were included for analysis. Periodontitis was associated with more hospitalization (p = 0.009), more days in the intensive care unit (ICU) (p = 0.042), admission to the semi-ICU (p = 0.047), and greater need for oxygen therapy (p = 0.042). After adjustment for confounders, periodontitis resulted in a 1.13-fold increase in the chance of hospitalization. Salivary IL-6 levels (p = 0.010) were increased in individuals with COVID-19 and periodontitis. Periodontitis was associated with increased RANKL and IL-1ß after COVID-19. No significant changes were observed in the bacterial loads of the periodontopathogens Porphyromona gingivalis, Aggregatibacter actinomycetemcomitans, Tanerella forsythia, and Treponema denticola. CONCLUSIONS: Periodontitis was associated with worse COVID-19 outcomes, suggesting the relevance of periodontal care to reduce the burden of overall inflammation. Understanding the crosstalk between SARS-CoV-2 infection and chronic conditions such as periodontitis that can influence disease outcome is important to potentially prevent complications of COVID-19.

Antecubital perforating vein stent-grafting for radiocephalic arteriovenous fistula recovery: A case report.

Stent-grafts have been increasingly used in hemodialysis arteriovenous accesses, particularly in recurrent stenosis or in cases of vein rupture after percutaneous transluminal angioplasty (PTA). Although they limit neointimal hyperplasia, stenosis development at stent edges remains a concern. Despite their advantages, they are seldom used on the forearm veins due to fracture risk associated with elbow motion and the potential to limit cannulation sites. This report presents a novel application of stent-grafts in salvaging a radio-cephalic arteriovenous fistula in an 84-year-old male to treat a single outflow path at the elbow through a stenosed antecubital perforating vein, after failed PTA. The vascular access remained patent 18 months after the procedure, with no need for additional treatments at this target lesion, even though a PTA was required for juxta-anastomotic stenosis. This report highlights a possible further use of covered stents in arteriovenous vascular accesses.

Outflow Rescue of Elbow-Blockade Forearm Arteriovenous Fistulas: Outcomes of Open Surgical Techniques.

BACKGROUND: Venous scarring at the elbow is a common problem that can cause early and late forearm arteriovenous fistula (AVF) dysfunction in hemodialysis patients. However, any effort to prolong the long-term patency of distal vascular accesses could benefit the patient's survival, maximizing the use of restricted venous patrimony. This study aims to report a single-center experience in the recovery of distal autologous AVF with venous outflow obstruction at the elbow using different surgical techniques. METHODS: Retrospective observational study of all patients treated at a single vascular access center from January 2011 to March 2022, with dysfunctional forearm AVFs presenting with outflow stenosis or occlusions at the elbow treated by open surgery, using 3 different surgical techniques. Demographics and clinically relevant data were collected. Evaluated endpoints included primary, assisted primary, and secondary patency rates at 1 and 2 years. RESULTS: Twenty-three patients with elbow-blocked outflow forearm AVFs have been treated with a mean age of 64 ± 15 years. The majority (96%) had a radiocephalic fistula. The median time from vascular access creation to intervention was 34.5 months (12-216 months). A total of 24 procedures have been performed using 3 different surgical techniques for bypassing the obstructed venous outflow at the elbow. Technical success was achieved in 96% of the surgically treated patients. Primary and secondary patency rates at 1 year were 67.4% and 89.4%, respectively, and 52.9% and 82.0% at 2 years, with a median follow-up of 19 months (6-92 months). CONCLUSIONS: AVFs outflow stenosis or occlusions at the elbow not amenable to endovascular therapy could lead to vascular access abandonment. Our study demonstrates multiple surgical solutions to avoid this adverse outcome. Elbow venous outflow surgical reconstruction seems effective for distal vascular access preservation. Close surveillance is essential for timely endovascular treatment of newly developed stenosis at the venous drainage.

Kidney autotransplantation as a key solution for a BEVAR type IIIb endoleak.

OBJECTIVES: Target vessel endoleaks are one of the most common causes of revision procedures after a fenestrated or branched endovascular aneurysm repair. Usually, a redo stenting is an effective therapy, however, not always feasible. We present a case of a hybrid treatment for a type IIIb endoleak using the renal autotransplantation technique. METHODS: A 60-year-old man with a thoracoabdominal aortic aneurysm has been treated with a custom-made branched endoprosthesis. Occlusion of the bridging stent to the right renal artery with total infarction of the right kidney was identified one week later and conservatively managed. After four years, a type IIIb endoleak was identified. Endovascular treatment was attempted unsuccessfully. So, the endoleak was corrected using a hybrid strategy with the kidney autotransplantation technique. RESULTS: A left kidney autotransplantation followed by an aortic stent-graft relining with a tubular graft has been done uneventfully, in a phased manner. Postoperative computed tomography angiography confirmed the patency of vascular reconstructions with no endoleaks. No adverse events occurred during one year of follow-up. CONCLUSION: Our case highlights kidney autotransplantation as a viable solution for a hybrid treatment of target vessel endoleaks and shows that this technique can assist complex endovascular aortic reconstructions.

Ruptured arteriovenous fistula pseudoaneurysm treatment by balloon-assisted direct percutaneous thrombin injection.

We present the case of a male patient on hemodialysis with a ruptured pseudoaneurysm in a brachiocephalic arteriovenous fistula (AVF) and with edema and pain in the right arm attended to in the emergency department. An ultrasonographic scan identified a ruptured pseudoaneurysm with hemorrhagic infiltration of the arm muscular tissues. We performed a percutaneous ultrasound-guided thrombin injection with an angioplasty balloon inflated in the lumen of the AVF achieving the pseudoaneurysm thrombosis. After 6 months of follow-up, the patient's arteriovenous access remains functional. Percutaneous ultrasound-guided thrombin injection assisted by an angioplasty balloon may be a good alternative to surgical intervention in the treatment of symptomatic growing pseudoaneurysms of the arteriovenous fistula with the benefit of preserving the vascular access.

Influence of tendon injuries on the clinical outcome of ankle and hindfoot fractures.

BACKGROUND: Associations of tendon injuries with ankle and hindfoot fractures is a current concern and recent research has linked specific fractures with specific tendon injuries, despite its functional impact being unknown. The purpose of this study is to assess that impact. METHODS: Computed tomography scans of patients with ankle and hindfoot fractures were reviewed for tendon injuries. Patients were clinically evaluated with the Visual Analogue Scale (VAS) and the Manchester-Oxford Foot Questionnaire (MOXFQ), via a telephonic interview. RESULTS: Eighty-five patients were included in the study. The mean age was of 49.9 ± 16.5 (14-80) years and there were 43 females (50,6%). Mean follow-up was of 43,7 ± 15,1 (24,4-82,2) months. Tendon injuries were identified in 23 patients (27,1%) and the most common lesion was tendon entrapment. The tibialis posterior tendon (TP) was injured in 18 patients (21,2%) and comprised 58,1% of all tendon injuries. Tendon injuries were mostly associated with pilon fractures, which was the most common fracture type (44,7%). There was no clinical difference between patients with a tendon injury [VAS of 4,3 ± 2,6 (0-8) and MOXFQ score of 35,1 ± 22,4 (5-80)], and those without [VAS of 3,9 ± 2,5 (0-10) and MOXFQ of 34,3 ± 26,0 (0-95), respectively (p = 0,281 and 0,689)]. CONCLUSION: Tendon injuries were present in 27% of patients with ankle and hindfoot injuries. The most frequently injured tendon was the TP in association with pilon fractures, with entrapment being the most common lesion. These lesions, however, do not seem to reflect in a worse functional outcome at two years of follow-up.

IL-21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21-treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.

Emergent Endovascular Treatment in Primary Ilio-enteric Fistula.

Aortoenteric fistula (AEF) is a rare cause of gastrointestinal (GI) bleeding. If not promptly diagnosed and treated, the associated mortality is very high. The role of endovascular treatment is not yet defined. In this article, we report a clinical case of a 94-year-old male patient admitted in the emergency department with rectal bleeding. Owing to the detection of a pulsatile abdominal mass, a computed tomography angiography (CTA) scan was performed, which established the diagnosis of aorto-enteric fistula due to a left common iliac artery aneurysm (CIAA) ruptured to the sigmoid colon and also revealed an abdominal aortic aneurysm (AAA) and an internal iliac artery aneurysm (IIAA). Given the age of the patient, general condition and technical difficulty inherent to the treatment of the IIAA by conventional surgery, we chose endovascular treatment. However, we wanted to avoid contact between the endograft and the colon orifice because of the risk of infection. The patient was treated emergently with an aorto-right uni-iliac graft and a femoro-femoral bypass, IIAA embolization and 2 left iliac excluders (at the origin of the common iliac and distally in the external iliac artery). It was decided to treat colon lesion conservatively. In this case, the aorto-uni-iliac graft excluded the aortic inline flow, the distal occluder prevented retrograde flow from the external iliac, and the embolization prevented retrograde flow and treated the IIAA. This way, no arterial pressure and no prosthetic material existed inside the ruptured artery, hopefully allowing the spontaneous closing of the orifice leading the sigmoid colon to heal. The postoperative period was uneventful, and the patient was discharged at the 8th postoperative day. The patient outcome is a strong argument on the merit of the treatment strategy.

Effectiveness and Safety of Rivaroxaban Compared to Acenocumarol after Infrainguinal Surgical Revascularization.

BACKGROUND: Optimal antithrombotic therapy after lower limb infrainguinal revascularization remains a controversial topic. The use of anticoagulants, alone or in combination with antiplatelet drugs, can potentially improve patency rate and limb salvage, particularly in patients with risk factors for early thrombosis. Bleeding is the main complication of long-term anticoagulant use. New oral anticoagulants can represent an attractive alternative to the standard vitamin K antagonists. The objective of the study is to evaluate the effectiveness (bypass occlusion and major amputation) and safety (major bleeding and all-cause mortality) of rivaroxaban compared to acenocumarol after infrainguinal lower limb surgical revascularization. MATERIAL AND METHODS: Retrospective cohort study of patients with peripheral arterial disease submitted to lower limb infrainguinal bypass revascularization with vein or expanded polytetrafluoroethylene conduit, who were anticoagulated with acenocumarol or rivaroxaban after hospital discharge. Patients with proximal revascularization, revascularization due to any pathology other than peripheral arterial disease, coagulation disorder, stroke or acute myocardial infarction in less than 30 days, glomerular filtration rate <15 mL/min, or on hemodialysis were excluded. RESULTS: One hundred nine patients were included (78.9% male), with a mean age of 64.8 years. After hospital discharge, 40 patients (36.7%) were medicated with rivaroxaban and 69 patients (63.3%) with acenocumarol. At 1 year of follow-up, patients under rivaroxaban and acenocumarol presented comparable major amputation rates (12.5 % vs. 10.1%, P = 0.756), bypass occlusion (22.5% vs. 24.6 %, P = 0.769), and mortality rate (10% vs. 8.7%, P = 0.756). Major bleeding occurred in 13.8% of patients. Patients with renal dysfunction had significantly higher bleeding risk with acenocumarol (45.5% vs. 0%, P = 0.028) compared to rivaroxaban, while patients with normal renal function presented similar bleeding rates with both anticoagulants (6.1% vs. 6.4%, P = 0.953). CONCLUSIONS: Rivaroxaban has equivalent effectiveness to acenocumarol after infrainguinal bypass revascularization, with similar occlusion, major amputation, and mortality rates. Rivaroxaban has an improved safety profile in patients with moderate renal dysfunction due to a significantly lower incidence of major bleeding. In patients with normal renal function, rivaroxaban and acenocumarol present equivalent major bleeding rates.

HAS-BLED Score Predicts the Risk of Major Bleeding in Chronic Anticoagulation after Lower Limb Surgical Revascularization.

BACKGROUND: Anticoagulant drugs are sometimes used after lower limb surgical bypass to improve patency. There are no bleeding risk scores validated specifically for patients with peripheral arterial disease. The HAS-BLED (hypertension, abnormal renal or liver function, stroke, history of or predisposition to bleeding, labile international normalized ratio (INR), elderly age [>65 years], and drugs or alcohol) score is a validated and frequently used tool to estimate the risk of major bleeding in patients receiving anticoagulation for atrial fibrillation. The objective of this study was to access the efficacy of the HAS-BLED score in predicting bleeding risk after lower limb bypass revascularization. METHODS: This study involved "secondary analysis of a retrospective database that includes patients with lower limb revascularization that was anticoagulated with acenocoumarol after hospital discharge." Consecutive patients treated between January 2014 and May 2016 were included. Patients previously on anticoagulants and patients on hemodialysis were excluded. RESULTS: Sixty-nine patients were included, 73.9% were males, with a mean age of 65 years. At 1-year follow-up, major bleeding occurred in 18.8% of patients. In this study, 52.1% of patients had HAS-BLED score ≥3. This subgroup had increased incidence of major bleeding: 33.3% compared to 0 risk factor (0%), 1 risk factor (0%), and 2 risk factors (4.2%) (P = 0.001). CONCLUSIONS: In this retrospective analysis, HAS-BLED score presented good association with major bleeding risk. It can be used as a tool for decision-making for the prescription of anticoagulants after lower limb revascularization. The prevalence of high scores is substantial, presuming high bleeding risk in this high-risk population.

Surgical Treatment of Cephalic Arch Stenosis through Rotation of the External Jugular Vein.

The percutaneous transluminal balloon angioplasty or cephalic vein transposition is the treatment for cephalic arch stenosis. In some cases, rotation of the external jugular vein may be a good option for the cephalic arch problems. We describe a new technique to treat cephalic arch stenosis. The technique enables the cephalic arch and subclavian vein to be bypassed altogether through the rotation of the external jugular vein. It consists of 3 small incisions, thus causing minimal surgical damage.

Prevalence and profile of users and non-users of anabolic steroids among resistance training practitioners.

BACKGROUND: To verify the prevalence and profile of users and non-users of anabolic steroid (AS) among resistance training practitioners. METHODS: An observational, cross-sectional survey was performed in 100 gyms in Curitiba city, involving 5773 individuals and self-administered questionnaires. The chi-square and z-tests of proportions were used for comparison between the groups (p < 0.05). RESULTS: 83.2% did not use, 9.1% formerly used, 3.4% currently used, and 4.3% intended used AS. The prevalence of former or current AS users was 16.9 and 6.5% among men and women, respectively. The prevalence ratios were as follows: 1) 2.6 male users for each woman; 2) 3.3 individuals aged 30-44 years and 2.8 individuals aged 18-29 years for each individual aged over 45 years. Beginners were not interested in using AS, but individuals who had trained longer had higher prevalence of AS use. CONCLUSIONS: The gym environment encouraged the use of AS owing to aesthetic appeal. Thus, suggesting the need for actions to prevent abusive use of AS considering the practitioners profile (practitioners were young, university and single).

Internal Carotid Artery Tortuosity as a Rare Cause of Dysphagia: Case Report and Literature Review.

Abnormalities in the morphology of internal carotid artery are commonly identified but their natural history is not well known. Rarely, vascular abnormalities can cause mass effect causing dysphagia. We report the case of a patient presenting with long-standing dysphagia and choking during swallowing of solid food caused by an internal carotid artery tortuosity undergoing surgical treatment at our institution and we review the available literature.