Reverse shoulder arthroplasty or nothing for patients with displaced proximal humeral fractures: a randomized controlled trial.

BACKGROUND: The benefits of reverse shoulder arthroplasty compared to nonoperative treatment for patients presenting with complex proximal fractures have been rarely explored. The aim of this prospective study was to compare the functional results of reverse shoulder arthroplasty with those of nonsurgical treatment in patients with displaced proximal humeral fractures. METHODS: A multicentric prospective randomized control trial of patients older than 70 years who sustained an acute proximal humeral fracture (3 or 4 parts), with less than 3 weeks of evolution, and had no previous condition or surgery on the affected shoulder was conducted. Patients were randomly assigned to the intervention group (implantation of a reverse shoulder arthroplasty and tuberosities reattachment) or the control group (nonoperative treatment). Functional outcome was assessed using the Constant-Murley score (CMS) at the 1-year follow-up. Complications and reinterventions were considered secondary outcomes. The power of the study relied on the inclusion of 81 patients to recognize a statistically significant difference of 10 points between CMS scores in the groups. Analysis was performed based on the intention to treat principle. RESULTS: Eighty-one patients were randomized to surgical treatment or nonoperative treatment, while 66 patients completed the 1-year follow-up evaluation. There was no significant difference between the groups in terms of age (76.1 yo vs. 77.43 yo, P = .43), sex (81.08% women in the surgical group vs. 84.09% in the nonoperative group, P = .72), or type of fracture according to Neer's classification system (P = .06). At the 1-year follow-up, the group assigned to undergo the intervention had better functional outcomes than the nonoperative treatment group (mean CMS; 61.24, SD: 13.33 vs. mean CMS: 52.44, SD: 16.22, P: .02), with a mean difference of 8.84 points, 95% CI (1.57, 16.11). Two patients in the intervention group (6.5%) suffered major complications (periprosthetic joint infection and axillary nerve palsy). No major complications were observed in the nonoperative group. One patient in the intervention group underwent secondary surgery for a periprosthetic joint infection. CONCLUSIONS: Treatment with reverse shoulder arthroplasty provides superior functional outcomes compared with conservative treatment for patients presenting with an acute proximal humeral fracture. The difference in CMS is close to the clinically significant thresholds, and some harms are associated with the operative treatment.

Intestinal metastases of colorectal cancer.

We present the case of an 82-year-old woman with a history of well-differentiated adenocarcinoma of the cecum, stage pT3N1M0, treated ten years before with right hemicolectomy and adjuvant chemotherapy (Capecitabine and Bevacizumab). She developed painless obstructive jaundice of sudden onset. Computed tomography (CT) showed an ampullary nodule with secondary dilatation of the biliary and the pancreatic ducts. Subsequent duodenoscopy and endoscopic ultrasound identified the presence of multiple 3-10 mm tumor-like nodules from the first to the second duodenal knee, the largest one infiltrating the papillary area and preventing its cannulation. Biopsy revealed a moderately differentiated adenocarcinoma with cribriform, nidiform and acinar architectural patterns and positive immunohistochemistry for CK20 and CDX2, compatible with colon origin. The patient was treated with five cycles of chemotherapy (FOLFOX) with the disappearance of the duodenal nodules, although during follow-up she developed disease progression with a left adnexal metastasis with identical histological and immunohistochemical pattern.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

Unraveling the peripheral and local role of inflammatory cytokines in glioblastoma survival.

Glioblastoma (GBM) is a life-threatening disease that presents high morbidity and mortality. The standardized treatment protocol results in a global survival of less than three years in the majority of cases. Immunotherapies have gained wide recognition in cancer treatment; however, GBM has an immunosuppressive microenvironment diminishing the possible effectiveness of this therapy. In this sense, investigating the inflammatory settings and the tumoral nature of GBM patients are an important goal to create an individual plan of treatment to improve overall survival rate and quality of life of these patients. Thirty-two patients who underwent surgical resection of GBM were included in this study. Tumor samples and 10 mL of peripheral blood were collected and immediately frozen. TNF-a, IL-1a and IL-4 were evaluated in the tumor and TNF-a, IL-1a and TGF-b in the plasma by Luminex assay. Immunohistochemistry analysis to determine immune celular profile was done, including immunohistochemistry for CD20, CD68 and CD3. Three cases were excluded. Tumor topography, tumor nature, and tumor volume reconstructions were accurately analyzed by T1-weighted, T2-weighted, and FLAIR magnetic resonance imaging. We found that GBM patients with below median peripheral levels of TNF-a and IL-1a had a decreased survival rate when compared to above median patients. On the other hand, patients with below median peripheral levels of TGF-b increased overall survival rate. Intratumoral IL-1a above median was associated with higher number of macrophages and fewer with B cells. Furthermore, plasmatic TNF-a levels were correlated with intratumoral TNF-a levels, suggesting that peripheral cytokines are related to the tumoral microenvironment. Even though tumor size has no difference regarding survival rate, we found a negative correlation between intratumoral IL-4 and tumor size, where larger tumors have less IL-4 expression. Nevertheless, the tumoral nature had a significant effect in overall survival rate, considering that infiltrative tumors showed decreased survival rate and intratumoral TNF-a. Moreover, expansive tumors revealed fewer macrophages and higher T cells. In multiple variation analyzes, we demonstrated that infiltrative tumors and below median peripheral IL-1a expression represent 3 times and 5 times hazard ratio, respectively, demonstrating a poor prognosis. Here we found that peripheral cytokines had a critical role as prognostic tools in a small cohort of GBM patients.

A Machine Learning Method to Identify the Risk Factors for Liver Fibrosis Progression in Nonalcoholic Steatohepatitis.

AIM: Nonalcoholic fatty liver disease (NAFLD) is a silent epidemy that has become the most common chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD, which is linked to a high risk of cirrhosis and hepatocellular carcinoma. The aim of this study is to develop a predictive model to identify the main risk factors associated with the progression of hepatic fibrosis in patients with NASH. METHODS: A database from a multicenter retrospective cross-sectional study was analyzed. A total of 215 patients with NASH biopsy-proven diagnosed were collected. NAFLD Activity Score and Kleiner scoring system were used to diagnose and staging these patients. Noninvasive tests (NITs) scores were added to identify which one were more reliable for follow-up and to avoid biopsy. For analysis, different Machine Learning methods were implemented, being the eXtreme Gradient Booster (XGB) system the proposed algorithm to develop the predictive model. RESULTS: The most important variable in this predictive model was High-density lipoprotein (HDL) cholesterol, followed by systemic arterial hypertension and triglycerides (TG). NAFLD Fibrosis Score (NFS) was the most reliable NIT. As for the proposed method, XGB obtained higher results than the second method, K-Nearest Neighbors, in terms of accuracy (95.05 vs. 90.42) and Area Under the Curve (0.95 vs. 0.91). CONCLUSIONS: HDL cholesterol, systemic arterial hypertension, and TG were the most important risk factors for liver fibrosis progression in NASH patients. NFS is recommended for monitoring and decision making.

Intensive 90-day textile wearable Holter monitoring: an alternative to detect paroxysmal atrial fibrillation in selected patients with cryptogenic stroke.

We aimed to demonstrate the feasibility of 90-day cardiac monitoring with an external Holter device and to find a target population able to benefit from such a technique. Cryptogenic stroke patients were continuously monitored for 90 days with a textile wearable Holter (TWH). Compliance and quality of the monitoring were assessed by the number of hours of ECG stored per month. Mean predictors of pAF, including age, gender, stroke severity, and atrial size (LAVI), were evaluated. One-year follow-up assessed pAF detection outside per protocol monitoring. Out of 224 patients included in 5 stroke centers, 163 patients (72.76%) fulfilled the criteria for the protocol. Median monitoring time was similar among the three months. Per protocol pAF detection reached 35.37% at 90 days. The age (OR 1.095; 95% CI 1.03-1.14) and the LAVI (OR 1.055; 95% CI 1.01-1.09) independently predicted pAF. The cut-off point of 70 years (AUC 0.68) (95% CI 0.60-0.76) predicted pAF with a sensitivity of 75.8% and specificity of 50.5%. The LAVI cut-off point of 28.5 (AUC 0.67) (95% CI 0.56-0.77) had a sensitivity of 63.6% and a specificity of 61.8% to detect pAF. The combination of both markers enhanced the validity of pAF detection sensitivity to 89.6%, with a specificity of 27.59%. These patients had increased risk of pAF during the 90-day monitoring HR 3.23 (χ2 7.15) and beyond 90 days (χ2 5.37). Intensive 90-days TWH monitoring detected a high percentage of pAF. However, a significant number of patients did not complete the monitoring. Patients older than 70 years and with enlarged left atria benefitted more from the protocol.

Unravelling the Role of Habenula Subnuclei on Avoidance Response: Focus on Activation and Neuroinflammation.

Understanding the mechanisms responsible for anxiety disorders is a major challenge. Avoidance behavior is an essential feature of anxiety disorders. The two-way avoidance test is a preclinical model with two distinct subpopulations-the good and poor performers-based on the number of avoidance responses presented during testing. It is believed that the habenula subnuclei could be important for the elaboration of avoidance response with a distinct pattern of activation and neuroinflammation. The present study aimed to shed light on the habenula subnuclei signature in avoidance behavior, evaluating the pattern of neuronal activation using FOS expression and astrocyte density using GFAP immunoreactivity, and comparing control, good and poor performers. Our results showed that good performers had a decrease in FOS immunoreactivity (IR) in the superior part of the medial division of habenula (MHbS) and an increase in the marginal part of the lateral subdivision of lateral habenula (LHbLMg). Poor performers showed an increase in FOS in the basal part of the lateral subdivision of lateral habenula (LHbLB). Considering the astroglial immunoreactivity, the poor performers showed an increase in GFAP-IR in the inferior portion of the medial complex (MHbl), while the good performers showed a decrease in the oval part of the lateral part of the lateral complex (LHbLO) in comparison with the other groups. Taken together, our data suggest that specific subdivisions of the MHb and LHb have different activation patterns and astroglial immunoreactivity in good and poor performers. This study could contribute to understanding the neurobiological mechanisms responsible for anxiety disorders.

Sclerosing angiomatoid nodular transformation, a rare splenic tumor with increasing incidence.

SANT (sclerosing angiomatoid nodular transformation) tumor is a rare splenic tumor of unknown etiology and vascular lineage, first described in 2004. Most cases are asymptomatic, although cases of anemia or abdominal pain in association with growth have been described. Spontaneous ruptures have not been described. Radiologically it presents a radial pattern with centripetal filling in dynamic MRI, being a characteristic feature, but not pathognomonic. It may present hypermetabolism in PET-CT. Its incidence is increasing since its description as an independent clinical and histopathological entity, especially in the oncological patients follow-up. Due to its radiological resemblance to metastatic lesions and its growth despite being a vascular lesion, splenectomy is indicated following the principles of oncologic surgery until a definitive diagnosis is made. It presents a benign behavior, requiring neither treatment nor specific subsequent surveillance. Two diagnosed cases of SANT are presented, as well as a review of the clinical, radiological and histopathological characteristics of this little-known splenic lesion.

Dominant marine heterotrophic flagellates are adapted to natural planktonic bacterial abundances.

Grazing controls bacterial abundances and composition in many ecosystems. In marine systems, heterotrophic flagellates (HFs) are important predators. Assemblages of HFs are primarily formed by species still uncultured; therefore, many aspects of their trophic behaviour are poorly known. Here, we assessed the functional response of the whole assemblage and of four taxa grown in an unamended seawater incubation. We used fluorescently labelled bacteria to create a prey gradient of two orders of magnitude in abundance and estimated ingestion rates. Natural HFs had a half-saturation constant of 6.7 × 105 prey ml-1 , a value lower than that of cultured flagellates and within the range of marine planktonic bacterial abundances. Minorisa minuta was well adapted to low prey abundances and very efficient in ingesting bacteria. MAST-4 and MAST-7 were also well adapted to the typical marine abundances but less voracious. In contrast, Paraphysomonas imperforata, a typical cultured species, did not achieve ingestion rate saturation even at the highest prey concentration assayed. Our study, beside to set the basis for the fundamental differences between cultured and uncultured bacterial grazers, indicate that the examined predator taxa have different functional responses, suggesting that they occupy distinct ecological niches according to their grazing strategies and prey preferences.

Acremonium (Sarocladium) periprosthetic joint infection: case report, literature review, and proposed antifungal regimen.

BACKGROUND: Fungal periprosthetic joint infections are rare. Acremonium osteoarticular infections are scarcely reported. Variable susceptibility to antifungal agents have been reported and optimal pharmacotherapy has yet to be established. Here we illustrate an Acremonium osteoarticular infection involving a prosthetic joint and present an antifungal regimen that had led to treatment success. CASE PRESENTATION: A 60-year-old female with a body mass index (BMI) of 40 had left total knee arthroplasty done in 2012 with a cementless implant for knee osteoarthritis. In 2019, the patient had asymptomatic, progressive osteolysis with fracture and migration of the femoral component warranting replacement. Eleven months later, the patient developed significant pain, redness, and swelling in the left leg and knee concerning for periprosthetic joint infection that failed outpatient antibiotic treatment. Further investigation revealed infection by Acremonium species. A revision of the joint was successfully completed, and the patient was placed on voriconazole for one year. Subsequent cultures did not yield any fungal growth. CONCLUSION: While an optimal antifungal regimen for periprosthetic joint infections has not been well established, voriconazole is a relatively safe and effective agent that can be used as a long-term therapy. With variable susceptibility testing in reported isolates, individualized antifungal susceptibility should be used to guide therapy for Acremonium infections.

Long-Term Follow-Up on Bilateral Posterior Hypothalamic Deep Brain Stimulation for Treating Refractory Aggressive Behavior in a Patient with Cri du Chat Syndrome: Analysis of Clinical Data, Intraoperative Microdialysis, and Imaging Connectomics.

Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.

Acoustic Noise-Based Detection of Ferroresonance Events in Isolated Neutral Power Systems with Inductive Voltage Transformers.

Power-quality events and operation transients in power systems (PS) with isolated neutral can saturate inductive voltage transformers (IVT), which, when interacting with the overhead and underground cable capacitances, can cause ferroresonance events in the local PS. This abnormal operating mode can partially or totally damage the transformers and switchgears within the affected PS. Distribution system operators (DSO) can minimize these effects by detecting ferroresonance events accurately and fast enough and changing the mode of operation accordingly. Direct detection methods, i.e., based on voltage measurements, are reliable, but the massive deployment of this solution is relatively expensive; i.e., power quality analyzers cost thousands of USD. Alternatively, indirect detection methods are also available, e.g., IVT vibration measurements with accelerometers costing hundreds of USD, but their reliability depends on the installation method used. This manuscript proposes using the acoustic noise caused by magnetostriction forces within the IVT core during ferroresonance events to detect their occurrence. Compared to other indirect methods, electret condenser microphones with preamplifying stage cost less than USD 10 and are less sensitive to the installation procedure. The proposed method is validated experimentally, and its performance compared to IVT vibration measurements one by using the same detection methodology.

Effect of Subthalamic Stimulation and Electrode Implantation in the Striatal Microenvironment in a Parkinson's Disease Rat Model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered the gold-standard treatment for PD; however, underlying therapeutic mechanisms need to be comprehensively elucidated, especially in relation to glial cells. We aimed to understand the effects of STN-microlesions and STN-DBS on striatal glial cells, inflammation, and extracellular glutamate/GABAergic concentration in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Rats with unilateral striatal 6-OHDA and electrodes implanted in the STN were divided into two groups: DBS OFF and DBS ON (5 days/2 h/day). Saline and 6-OHDA animals were used as control. Akinesia, striatal reactivity for astrocytes, microglia, and inflammasome, and expression of cytokines, cell signaling, and excitatory amino acid transporter (EAAT)-2 were examined. Moreover, striatal microdialysis was performed to evaluate glutamate and GABA concentrations. The PD rat model exhibited akinesia, increased inflammation, glutamate release, and decreased glutamatergic clearance in the striatum. STN-DBS (DBS ON) completely abolished akinesia. Both STN-microlesion and STN-DBS decreased striatal cytokine expression and the relative concentration of extracellular glutamate. However, STN-DBS inhibited morphological changes in astrocytes, decreased inflammasome reactivity, and increased EAAT2 expression in the striatum. Collectively, these findings suggest that the beneficial effects of DBS are mediated by a combination of stimulation and local microlesions, both involving the inhibition of glial cell activation, neuroinflammation, and glutamate excitotoxicity.

Anticoagulation Therapy in Patients With Coronavirus Disease 2019: Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 [HOPE-COVID19]).

OBJECTIVES: No standard therapy, including anticoagulation regimens, is currently recommended for coronavirus disease 2019. Aim of this study was to evaluate the efficacy of anticoagulation in coronavirus disease 2019 hospitalized patients and its impact on survival. DESIGN: Multicenter international prospective registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019). SETTING: Hospitalized patients with coronavirus disease 2019. PATIENTS: Five thousand eight hundred thirty-eight consecutive coronavirus disease 2019 patients. INTERVENTIONS: Anticoagulation therapy, including prophylactic and therapeutic regimens, was obtained for each patient. MEASUREMENTS AND MAIN RESULTS: Five thousand four hundred eighty patients (94%) did not receive any anticoagulation before hospitalization. Two-thousand six-hundred one patients (44%) during hospitalization received anticoagulation therapy and it was not associated with better survival rate (81% vs 81%; p = 0.94) but with higher risk of bleeding (2.7% vs 1.8%; p = 0.03). Among patients admitted with respiratory failure (49%, n = 2,859, including 391 and 583 patients requiring invasive and noninvasive ventilation, respectively), anticoagulation started during hospitalization was associated with lower mortality rates (32% vs 42%; p < 0.01) and nonsignificant higher risk of bleeding (3.4% vs 2.7%; p = 0.3). Anticoagulation therapy was associated with lower mortality rates in patients treated with invasive ventilation (53% vs 64%; p = 0.05) without increased rates of bleeding (9% vs 8%; p = 0.88) but not in those with noninvasive ventilation (35% vs 38%; p = 0.40). At multivariate Cox' analysis mortality relative risk with anticoagulation was 0.58 (95% CI, 0.49-0.67) in patients admitted with respiratory failure, 0.50 (95% CI, 0.49-0.67) in those requiring invasive ventilation, 0.72 (95% CI, 0.51-1.01) in noninvasive ventilation. CONCLUSIONS: Anticoagulation therapy in general population with coronavirus disease 2019 was not associated with better survival rates but with higher bleeding risk. Better results were observed in patients admitted with respiratory failure and requiring invasive ventilation.

Impact of social and mobility restrictions in Parkinson's disease during COVID-19 lockdown.

BACKGROUND: The consequences of strict COVID-19 mobility restrictions on motor/non-motor features in Parkinson's disease (PD) have not been systematically studied but worse mobility and quality of life have been reported. To elucidate this question, 12 mild to moderate PD patients were assessed in March 2020 before and after two months of isolation as part of a clinical study that had to be interrupted due to the pandemic and the implementation of COVID19 mobility restrictions. METHODS: Twelve patients were systematically evaluated before and after the lockdown period as part of a larger cohort that previously underwent thermal water rehabilitation. Clinical outcomes were the Body Mass index, the Mini-Balance Evaluation Systems Test, the MDS-Unified Parkinson's Disease Rating Scale part III, the 6 Minute Walking Test and the New Freezing of Gait Questionnaire. Global cognition was evaluated with the Montreal Cognitive Assessment scale. The impact of COVID-19 restrictions on quality of life and functional independence was evaluated with The Parkinson's disease Quality of life (PDQ-39), the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living questionnaires (IADL) and the Parkinson's disease cognitive functional rating scales (PD-CFRS). RESULTS: After two months of isolation the Mini-BESTest score worsened (p=0.005), and four patients reported one or more falls during the lockdown. BMI increased (p=0.031) while the remaining clinical variables including quality of life did not change. CONCLUSION: We observed moderate worsening at Mini-BESTest, greater risk of falls and increased body weight as consequence of prolonged immobility. We believe negative effects were partially softened since patients were in contact with our multidisciplinary team during the lockdown and had previously received training to respond to the needs of this emergency isolation. These findings highligh the importnace of patient-centered interventions in PD management.

Effects of a Fruit and Vegetable-Based Nutraceutical on Biomarkers of Inflammation and Oxidative Status in the Plasma of a Healthy Population: A Placebo-Controlled, Double-Blind, and Randomized Clinical Trial.

There is scientific evidence of the positive effect of polyphenols from plant foods on inflammation and oxidative status. The aim of the present study was to investigate whether treatment with a high-polyphenolic nutraceutical reduces the plasmatic concentration of certain oxidative and inflammatory biomarkers in a healthy population. One hundred and eight subjects were selected and stratified by sex in the intervention group (n = 53) and the placebo group (n = 55). Ninety-two subjects completed the study after two 16-week treatment periods separated by a four-week washout period. The results revealed statistically significant differences in subjects treated with the polyphenolic extract compared to the placebo: A decrease in homocysteine, oxidized low-density lipoprotein (OxLDL), TNF-α, sTNFR1, and C-reactive protein (CRP). The most significant decrease was observed for OxLDL (from 78.98 ± 24.48 to 69.52 ± 15.64; p < 0.05) and CRP (from 1.50 ± 0.33 to 1.39 ± 0.37; p < 0.05), both showing significant differences compared to the placebo (p < 0.001). Moreover, catecholamines increased after the administration of the product under investigation, especially in the case of dopamine (from 15.43 ± 2.66 to 19.61 ± 5.73; p < 0.05). Therefore, the consumption of a nutraceutical based on fruit and vegetables with a high polyphenol content seems to improve the parameters related to health benefits (oxidative and inflammatory biomarkers), including remarkable changes in the expression of catecholamines.

Autoreactive B-lymphocytes in SLE and RA patients: Isolation and characterisation using extractable nuclear and citrullinated antigens bound to immunobeads.

Systemic lupus erythematosus and rheumatoid arthritis are autoimmune diseases characterised by B-cell hyperactivation and production of autoantibodies (AutoAbs) against various self-antigens, including extractable nuclear antigens and citrullinated peptides. Therefore, B lymphocytes and antibody-secreting cells are considered relevant targets for therapies. However, isolation and characterisation of auto-reactive specific B lymphocytes are limited, primarily due to technical issues. In this work, we purified extractable nuclear antigen-specific and citrullinated peptide-specific auto-reactive B lymphocytes by magnetic selection with ENA- and citrullinated peptide-bound immunobeads. We obtained blood auto-reactive B lymphocytes from most patients. Their nature was primarily naïve B cells, some of them in an active status, with low levels of somatic hypermutations in the immunoglobulin heavy-chain variable regions. Their presence correlated with serum levels of autoAb. Auto-reactive B lymphocytes were able to differentiate into auto-reactive antibody-secreting cells under conditions of stimulation. In addition, based on the presence of circulating auto-reactive B cells and/or antibody-secreting cells, four different profiles were described in lupus patients. Thus, tracking auto-reactive B cells and/or antibody-secreting cells in patient blood could represent a biomarker for deciding whether to use therapies blocking either B cells, plasma cells or both, as well as a new tool for monitoring minimal residual autoimmune disease in patients.

Bronchoscopist's perception of the quality of the single-use bronchoscope (Ambu aScope4™) in selected bronchoscopies: a multicenter study in 21 Spanish pulmonology services.

BACKGROUND: The disposable bronchoscope is an excellent alternative to face the problem of SARS-CoV-2 and other cross infections, but the bronchoscopist's perception of its quality has not been evaluated. METHODS: To evaluate the quality of the Ambu-aScope4 disposable bronchoscope, we carried out a cross-sectional study in 21 Spanish pulmonology services. We use a standardized questionnaire completed by the bronchoscopists at the end of each bronchoscopy. The variables were described with absolute and relative frequencies, measures of central tendency and dispersion depending on their nature. The existence of learning curves was evaluated by CUSUM analysis. RESULTS: The most frequent indications in 300 included bronchoscopies was bronchial aspiration in 69.3% and the median duration of these was 9.1 min. The route of entry was nasal in 47.2% and oral in 34.1%. The average score for ease of use, image, and aspiration quality was 80/100. All the planned techniques were performed in 94.9% and the bronchoscopist was satisfied in 96.6% of the bronchoscopies. They highlighted the portability and immediacy of the aScope4TM to start the procedure in 99.3%, the possibility of taking and storing images in 99.3%. The CUSUM analysis showed average scores > 70/100 from the first procedure and from the 9th procedure more than 80% of the scores exceeded the 80/100 score. CONCLUSIONS: The aScope4™ scored well for ease of use, imaging, and aspiration. We found a learning curve with excellent scores from the 9th procedure. Bronchoscopists highlighted its portability, immediacy of use and the possibility of taking and storing images.

808 nm-activable core@multishell upconverting nanoparticles with enhanced stability for efficient photodynamic therapy.

BACKGROUND: The unique upconversion properties of rare-earth-doped nanoparticles offers exciting opportunities for biomedical applications, in which near-IR remote activation of biological processes is desired, including in vivo bioimaging, optogenetics, and light-based therapies. Tuning of upconversion in purposely designed core-shell nanoparticles gives access to biological windows in biological tissue. In recent years there have been several reports on NIR-excitable upconverting nanoparticles capable of working in biological mixtures and cellular settings. Unfortunately, most of these nanosystems are based on ytterbium's upconversion at 980 nm, concurrent with water's absorption within the first biological window. Thus, methods to produce robust upconverting nanoplatforms that can be efficiently excited with other than 980 nm NIR sources, such as 808 nm and 1064 nm, are required for biomedical applications. RESULTS: Herein, we report a synthetic method to produce aqueous stable upconverting nanoparticles that can be activated with 808 nm excitation sources, thus avoiding unwanted heating processes due to water absorbance at 980 nm. Importantly, these nanoparticles, once transferred to an aqueous environment using an amphiphilic polymer, remain colloidally stable for long periods of time in relevant biological media, while keeping their photoluminescence properties. The selected polymer was covalently modified by click chemistry with two FDA-approved photosensitizers (Rose Bengal and Chlorin e6), which can be efficiently and simultaneously excited by the light emission of our upconverting nanoparticles. Thus, our polymer-functionalization strategy allows producing an 808 nm-activable photodynamic nanoplatform. These upconverting nanocomposites are preferentially stored in acidic lysosomal compartments, which does not negatively affect their performance as photodynamic agents. Upon 808 nm excitation, the production of reactive oxidative species (ROS) and their effect in mitochondrial integrity were demonstrated. CONCLUSIONS: In summary, we have demonstrated the feasibility of using photosensitizer-polymer-modified upconverting nanoplatforms that can be activated by 808 nm light excitation sources for application in photodynamic therapy. Our nanoplatforms remain photoactive after internalization by living cells, allowing for 808 nm-activated ROS generation. The versatility of our polymer-stabilization strategy promises a straightforward access to other derivatizations (for instance, by integrating other photosensitizers or homing ligands), which could synergistically operate as multifunctional photodynamic platforms nanoreactors for in vivo applications.

Raising awareness about microbial antibiotic resistance in undergraduate dental students: a research-based strategy for teaching non-laboratory elements of a microbiology curriculum.

BACKGROUND: Resistance to antimicrobial agents has become a problem in modern society. Antibiotic resistant bacteria undermine the prevention and treatment of infections. Undergraduate dental students in Europe are required to receive information in aspects of microbiology relevant for dental practice, including oral microbial pathogens and resistance mechanisms against antimicrobial compounds. The objective of this study was to implement a research-based strategy to aid the understanding of the increase in antimicrobial resistance in undergraduate dental student training. The primary outcome of this project is the efficacious delivery of the learning objectives. METHODS: Ten volunteer undergraduate student "ambassadors" were recruited to manage the project with assistance from lead academics. Student ambassadors were a source of peer learning for their colleagues. The project consisted of three phases: Pre-project preparation (in which the ambassadors received special instruction and training); Practical experience (in which the ambassadors worked with volunteer student colleagues to carry out the project); Public presentation of results (in which ambassadors presented study results at a scientific conference of their choosing). RESULTS: A total of 1164 students volunteered for the project, corresponding to an average participation rate of 76.4% students per year of the course. Following final debriefing, student participants and ambassadors were strongly positive in their evaluation of the achievement of 8 key student learning objectives. The results demonstrate that most volunteers improved their knowledge related to antimicrobial resistance mechanisms in microbiology. Additional benefits of participation in this project included an improvement in dental knowledge and ethics in biomedical research for the student volunteers, whilst the student ambassadors reported improved knowledge about critical thinking and study design, as well as a deeper understanding about microbiological analysis methods. CONCLUSIONS: To the best of our knowledge, this the first instance of the application of project-based methodologies to the teaching of a traditionally non-laboratory component of a subject taught in the dentistry curriculum. Results from both students and ambassadors highlighted the increase in dental knowledge and an increased awareness of antimicrobial resistance as the key outcomes of this project.