The Antinociceptive Responses of MTDZ to Paclitaxel-Induced Peripheral Neuropathy and Acute Nociception in Mice: Behavioral, Pharmacological, and Biochemical Approaches.

The efficacy of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5] thiodiazole (MTDZ) in mitigating paclitaxel (PTX)-induced peripheral neuropathy was investigated in male and female Swiss mice. The study examined the effects of MTDZ on various pathways, including transient receptor potential cation channel subfamily V member 1 (TRPV1), glutamatergic, nitrergic, guanylate cyclase (cGMP), serotonergic, and opioidergic. Mice received intraperitoneal PTX (2 mg/kg) or vehicle on days 1, 2, and 3, followed by oral MTDZ (1 mg/kg) or vehicle from days 3 to 14. Mechanical and thermal sensitivities were assessed using Von Frey and hot plate tests on days 8, 11, and 14. The open field test evaluated locomotion and exploration on day 12. On day 15, nitrite and nitrate (NOx) levels and Ca2+-ATPase activity in the cerebral cortex and spinal cord were measured after euthanizing the animals. MTDZ administration reversed the heightened mechanical and thermal sensitivities induced by PTX in male and female mice without affecting locomotion or exploration. MTDZ also modulated multiple pathways, including glutamatergic, NO/L-arginine/cGMP, serotonergic (5-HT1A/1B), opioid, and TRPV1 pathways. Additionally, MTDZ reduced NOx levels and modulated Ca2+-ATPase activity. In conclusion, MTDZ effectively alleviated PTX-induced peripheral neuropathy and demonstrated multi-targeted modulation of pain-related pathways. Its ability to modulate multiple pathways, reduce NOx levels, and modulate Ca2+-ATPase activity makes it a potential pharmacological candidate for peripheral neuropathy, acute nociceptive, and inflammatory conditions. Further research is needed to explore its therapeutic potential in these areas.

Bacteremia following different oral procedures: Systematic review and meta-analysis.

To evaluate the timing, duration and incidence of bacteremia following invasive dental procedures (IDPs) or activities of daily living (ADL). Eight databases were searched for randomized (RCTs) and nonrandomized controlled trials (nRCTs) evaluating bacteremia before and after IDPs or ADL in healthy individuals. The risk of bias was assessed by RoB 2.0 and ROBINS-I. For the meta-analysis, the primary outcomes were the timing and duration of bacteremia. The secondary outcome was the incidence of bacteremia, measuring the proportion of patients with bacteremia within 5 min after the end of the procedure compared with baseline. We included 64 nRCTs and 25 RCTs. Peak bacteremia occurred within 5 min after the procedure and then decreased over time. Dental extractions showed the highest incidence of bacteremia (62%-66%), followed by scaling and root planing (SRP) (44%-36%) and oral health procedures (OHP) (e.g., dental prophylaxis and dental probing without SRP) (27%-28%). Other ADL (flossing and chewing) (16%) and toothbrushing (8%-26%) resulted in bacteremia as well. The majority of studies had some concerns RCTs or moderate risk of bias nRCTs. Dental extractions, SRP and OHP, are associated with the highest frequency of bacteremia. Toothbrushing, flossing, and chewing also caused bacteremia in lower frequency.

Anti-SARS-CoV-2 inactivated vaccine in patients with ANCA-associated vasculitis: Immunogenicity, safety, antibody decay and the booster dose.

OBJECTIVE: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. METHODS: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). RESULTS: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05‒0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05‒0.88, p = 0.034). After six months (D69‒D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. CONCLUSION: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698).

Anti-SARS-CoV-2 inactivated vaccine in patients with ANCA-associated vasculitis: Immunogenicity, safety, antibody decay and the booster dose

Abstract Objective: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. Methods: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). Results: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05-0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05-0.88, p = 0.034). After six months (D69-D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. Conclusion: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698).

Mechanistic pathways of fibromyalgia induced by intermittent cold stress in mice is sex-dependently.

Fibromyalgia results from a complex interplay of biochemical and neurobiological elements mediated sensitization of nociceptive pathways. Despite the symptoms of fibromyalgia negatively affect the quality of life of patients, the pathophysiology of this disease remains inconclusive, which difficult the development of an appropriate treatment. The present study investigated the involvement of the serotonergic receptors, the N-methyl-D-aspartate (NMDA)/ nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathway and the oxidative stress in an animal model of fibromyalgia induced by intermittent cold stress (ICS), considering the specificities of male and female Swiss mice. The ICS exposure increased mechanical and thermal sensitivities, and decreased muscle strength in mice of both sexes. Female mice exhibited a longer-lasting mechanical sensitivity than male mice exposed to ICS along with an enhancement of the Na+, K+-ATPase activity in the spinal cord and cerebral cortex. Conversely, an inhibition in the Na+, K+-ATPase and glutathione peroxidase activities accompanied by an increase in the reactive species levels in the cerebral cortex of male mice were observed. The treatment with different serotonergic antagonists (pindolol, ketanserin and ondasetron) reversed the mechanical sensitivity in mice of both sexes, after the ICS exposure. The administration of MK-801, L-arginine and methylene blue also blocked the mechanical sensitivity in female mice exposed to ICS. Except L-arginine, MK-801 and methylene blue also attenuated this nociceptive signal in male mice, after ICS exposure. In conclusion, the modulation of serotonergic receptors, the NMDA/NO/cGMP pathway, and the oxidative stress seems contribute to nociceptive behaviors induced by ICS exposure sex-dependent.

Indirectness (transferability) is critical when considering existing economic evaluations for GRADE clinical practice guidelines: a systematic review.

OBJECTIVES: Grading of Recommendations Assessment, Development and Evaluation (GRADE) practice guideline developers often perform systematic reviews of potential economic evaluations to inform recommendation decision-making. We aimed to identify indirectness characteristics of economic evaluations, related to GRADE evidence-to-decision (EtD) theoretical frameworks, that influence selection of these articles. STUDY DESIGN AND SETTING: MEDLINE, EMBASE, CINAHL, and EconLit were systematically searched to May 2020 to identify indirectness characteristics relevant for economic evaluation transferability to GRADE EtD theoretical frameworks. Four reviewers screened citations to identify articles of any type that explored study characteristics most important or relevant to economic evaluation transferability, restricted to English language we generated frequencies of article features, used thematic analysis to summarize study characteristics, and assessed certainty in the evidence using GRADE-CERQual. RESULTS: We included 57 articles, with a dearth of empirical literature-some may have been missed. We identified eight general themes and 28 subthemes most important to transferability from 41% of articles. Moderate-to-high confidence evidence suggested that GRADE EtD domains of population, intervention and comparison research question elements, resource use estimation and methodology, and provider and decision maker acceptability are most important indirectness study characteristics that economists consider when choosing economic evaluation outcomes for use in recommendation decision-making. CONCLUSION: We have identified factors important for guideline developers to consider when selecting economic evaluations as research evidence. An economic competency on the development team facilitates these endeavors. This supports the GRADE Working Group's tenant of transparent reporting or availability of sufficient information elsewhere to assess indirectness.

Contribution of Opioid and Nitrergic Systems to m-Trifluoromethyl diphenyl Diselenide Attenuates Morphine-Induced Tolerance in Mice.

m-Trifluoromethyl diphenyl diselenide (TFDD) has antinociceptive and antidepressant-like properties and attenuates morphine withdrawal signs in mice. This study investigated if TFDD affects the development of morphine tolerance to its antinociceptive and antidepressant-like effects in mice. We also investigated whether TFDD modulates signaling pathways related to morphine tolerance, including the opioid receptors and some parameters of the nitrergic system. Male adult Swiss mice received morphine alone (5 mg/kg, subcutaneous) and in combination with TFDD (10 mg/kg, intragastric) for 7 days. Mice were subjected to hot plate and forced swim tests on days 1, 3, 5, and 7 of the experimental protocol. Repeated TFDD administrations avoided tolerance development mediated by morphine, including its antinociceptive and antidepressant-like effects. A single morphine dose increased MOR and NOx but decreased iNOS contents in the mouse cerebral cortex. In turn, single morphine and TFDD co-administration restored the MOR and iNOS protein levels. On the other hand, morphine repeated doses enhanced DOR and reduced MOR and NOx contents, whereas the morphine and TFDD association reestablished DOR and NOx levels in the mouse cerebral cortex. In conclusion, some opioid and nitrergic system parameters might contribute to TFDD attenuation of antinociceptive and antidepressant-like tolerance induced by morphine in mice.

Occurrence of bruxism in individuals with autism spectrum disorder: A systematic review and meta-analysis.

AIMS: To investigate bruxism in individuals with autism spectrum disorder (ASD) and neurotypical individuals. METHODS AND RESULTS: Searches were conducted in the MedLine via Ovid, Embase via Ovid, Cochrane Database of Systematic Reviews, Scopus, Web of Science, Latin American and Caribbean Health Sciences (LILACS), Brazilian Library of Dentistry (BBO) and SciELO databases, grey literature and a hand search up to December 2020 with no restrictions imposed regarding language or year of publication (CRD42020211307). For the meta-analysis, the frequency of bruxism was extracted, with the calculation of odds ratios (OR) and 95% confidence intervals (CI) using a random effects model in RevManager. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Seventeen case-control studies were included in the qualitative synthesis and 15 were included in the meta-analysis, totaling a population of 3850 individuals. The ASD group was more likely to develop bruxism than the controls (OR: 3.80; 95% CI: 2.06-7.01). The certainty of the evidence was classified as "very low" for the occurrence of bruxism between ASD and control individuals. CONCLUSION: It is uncertain whether individuals with ASD are more likely to have bruxism than healthy controls.

Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+-ATPase, Oxidative Stress, and 7-Chloro-4-(phenylselanyl) quinoline Therapy.

Almost 90% of patients develop pain immediately after oxaliplatin (OXA) treatment. Here, the impact of aging on OXA-induced acute peripheral neuropathy and the potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) as a new therapeutic strategy were evaluated. In Swiss mice, the oxidative damage and its influence on Mg2+-ATPase and Na+, K+-ATPase activities were investigated. The relationship between the reactive oxygen species (ROS) and nitrate and nitrite (NOx) levels, the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) with the development of OXA-induced acute peripheral neuropathy was also studied. In this study, it was evidenced that OXA-induced acute peripheral neuropathy was exacerbated by aging through increased oxidative damage as well as Na+, K+-ATPase, and Mg+2-ATPase inhibition. 4-PSQ reversed hypersensitivity induced by OXA and aging-aggravated by reducing ROS and NOx levels, through modulation of GPx and SOD activities. 4-PSQ partially reestablish Na+, K+-ATPase activity, but not Mg 2+-ATPase activity. Locomotor and exploratory activities were not affected. This study is the first of its kind, providing new insight into the aging impact on mechanisms involved in OXA-induced acute peripheral neuropathy. Also, it provides evidence on promising 4-PSQ effects on this condition, mainly on aging.

Transdermal release of methotrexate by cationic starch/poly(vinyl alcohol)-based films as an approach for rheumatoid arthritis treatment.

Methotrexate (MTX) is a common drug used for rheumatoid arthritis (RA) treatment; however, a series of adverse effects associated with its oral or subcutaneous administration is reported. Transdermal delivery of MTX is an alternative to abate these issues, and the use of drug delivery systems (DDS) based on polymeric films presents an impressive potential for this finality. Based on this, in this study, we report the preparation of films made by cationic starch (CSt), poly(vinyl alcohol) (PVA), and chondroitin sulfate (ChS) to incorporate and release MTX, as well as the in vivo evaluation in model of rheumatoid arthritis in mice. CSt/PVA and CSt/PVA/ChS-based films (with and without MTX) were prepared using a simple protocol under mild conditions. The films loaded with 5 w/w-% of MTX exhibited appreciable drug loading efficiency and distribution. The MTX permeation through the layers of porcine skin demonstrated that most of the drug permeated was detected in the medium, suggesting that the formulation can provide a systemic absorption of the MTX. In vivo studies performed in an arthritis-induced model in mice demonstrated that the MTX-loaded films were able to treat and attenuate the symptoms and the biochemical alterations related to RA (inflammatory process, oxidative stress, and nociceptive behaviors). Besides, the pharmacological activity of MTX transdermally delivery by the CSt/PVA and CSt/PVA/ChS films was comparable to the MTX orally administered. Based on these results, it can be inferred that both films are prominent materials for incorporation and transdermal delivery of MTX in a practical and non-invasive manner.

Synthesis and Evaluation of Antioxidant, Anti-Edematogenic and Antinociceptive Properties of Selenium-Sulfa Compounds.

Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10 mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital.

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Organoselenium-chitosan derivative: Synthesis via "click" reaction, characterization and antioxidant activity.

The derivatization of chitosan (CS) is widely exploited to endow this polysaccharide with enhanced physicochemical and biological properties. Beyond the synthetic route, the nature of the compounds used to functionalize the CS-derivatives exerts a pivotal role in their final properties. Making use of a simple "click" reaction, we synthesized for the first time an organoselenium-CS derivative through a 1,2,3-triazole formation. The product (CS-TSe) was characterized in detail by FTIR, NMR (1H, 13C, and 77Se) and UV-Vis techniques, and SEM microscopy. The antioxidant activity of CS-TSe was examined by ABTS+ and DPPH (free radical-scavenging) assays. Experimentally, it was demonstrated that CS-TSe has superior antioxidant activity compared with raw CS and "free" organoselenium compound, suggesting a benign and synergistic effect due to the derivatization. In short, the antioxidant property of CS-TSe combined with the other attractive properties of CS and selenium could be useful in the formulation of advanced materials for biomedical and packaging applications.

Guidelines that use the GRADE approach often fail to provide complete economic information for recommendations: A systematic survey.

OBJECTIVE: Little is known about how developers and panel members report cost and cost effectiveness considerations in GRADE guideline Evidence-to-Decision (EtD) frameworks. A systematic survey was conducted to explore approaches and factors contributing to variability in economic information reporting. STUDY DESIGN AND SETTING: Guideline organization websites were systematically searched to create a convenience sample of guidelines. Reviewers screened published EtD frameworks and generated frequencies of reporting approaches. We used thematic analysis to summarize factors related to variability of economic information reporting. RESULTS: We included 142 guidelines. The overall rate of reporting economic information was high (91%); however, there was variability across completion of predefined EtD Likert-type judgments (70%), noting information as not identified across EtD framework domains (57%), and providing remarks to justify recommendations (38%). Six themes contributing to variability emerged, related to: intervention, population, payor, provider, healthcare resource use, and economic model building factors. Only 2 guidelines performed a GRADE certainty appraisal of economic outcomes. CONCLUSION: Completing predefined EtD Likert-type judgments, specifically reporting a literature review approach, study selection criteria and economic model building limitations, as well as linking these to recommendation justification remarks are potential areas for improved use, adoption and adaptation of recommendation, and transparency of GRADE EtD frameworks.

Systematic review and meta-analysis of outcomes in patients with suspected pulmonary embolism.

Prompt evaluation and therapeutic intervention of suspected pulmonary embolism (PE) are of paramount importance for improvement in outcomes. We systematically reviewed outcomes in patients with suspected PE, including mortality, incidence of recurrent PE, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included 22 studies with 15 865 patients. Among patients who were diagnosed with PE and discharged with anticoagulation, 3-month follow-up revealed that all-cause mortality was 5.69% (91/1599; 95% confidence interval [CI], 4.56-6.83), mortality from PE was 1.19% (19/1597; 95% CI, 0.66-1.72), recurrent venous thromboembolism (VTE) occurred in 1.38% (22/1597; 95% CI: 0.81-1.95), and major bleeding occurred in 0.90% (2/221%; 95% CI, 0-2.15). In patients with a low pretest probability (PTP) and negative D-dimer, 3-month follow-up revealed mortality from PE was 0% (0/808) and incidence of VTE was 0.37% (4/1094; 95% CI: 0.007-0.72). In patients with intermediate PTP and negative D-dimer, 3-month follow-up revealed that mortality from PE was 0% (0/2747) and incidence of VTE was 0.46% (14/3015; 95% CI: 0.22-0.71). In patients with high PTP and negative computed tomography (CT) scan, 3-month follow-up revealed mortality from PE was 0% (0/651) and incidence of VTE was 0.84% (11/1302; 95% CI: 0.35-1.34). We further summarize outcomes evaluated by various diagnostic tests and diagnostic pathways (ie, D-dimer followed by CT scan).

CF3-substituted diselenide modulatory effects on oxidative stress, induced by single and repeated morphine administrations, in susceptible tissues of mice.

Studies reveal that oxidative stress is associated with adverse effects of long-term morphine treatment. The m-trifluoromethyl-diphenyl diselenide (CF3) is a multi-target organoselenium compound that has antioxidant properties in different experimental models. This study aimed to investigate the CF3 effects against redox imbalance in peripheral and central tissues of mice, after single or multiple morphine doses. Swiss male mice received a single dose of morphine (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.), or morphine was repeatedly injected (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.) administered twice daily for 7 days. Oxidative stress was determined in the hippocampus, liver, and kidney. CF3 reversed the increase in reactive species caused by single and multiple morphine doses in the peripheral tissues. CF3 increased hepatic non-protein thiol levels and the superoxide dismutase (SOD) activity decreased by a single morphine dose. CF3 reversed the reduction in SOD activity in the kidney of mice repeatedly exposed to morphine. The study demonstrates that peripheral tissues were more susceptible than the hippocampus to oxidative stress induced by morphine in mice. The results show that CF3 modulated parameters of oxidative stress modified by single and multiple morphine administrations in peripheral and central tissues of mice.

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Synthesis of 2-Organylchalcogenopheno[2,3-b]pyridines from Elemental Chalcogen and NaBH4 /PEG-400 as a Reducing System: Antioxidant and Antinociceptive Properties.

An alternative method to prepare 2-organylchalcogenopheno[2,3-b]pyridines was developed by the insertion of chalcogen species (selenium, sulfur or tellurium), generated in situ, into 2-chloro-3-(organylethynyl)pyridines by using the NaBH4 /PEG-400 reducing system, followed by an intramolecular cyclization. It was possible to obtain a series of compounds with up to 93 % yield in short reaction times. Among the synthesized products, 2-organyltelluropheno[2,3-b]pyridines have not been described in the literature so far. Moreover, the compounds 2-phenylthieno[2,3-b]pyridine (3 b) and 2-phenyltelluropheno[2,3-b]pyridine (3 c) exhibited significant antioxidant potential in different in vitro assays. Further studies demonstrated that compound 3 b exerted an antinociceptive effect in acute inflammatory and non-inflammatory pain models, thus indicating the involvement of the central and peripheral nervous systems on its pharmacological action. More specifically, our results suggest that the intrinsic antioxidant property of compound 3 b might contribute to attenuating the nociception and inflammatory process on local injury induced by complete Freund's adjuvant (CFA).

Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis.

After deep vein thrombosis (DVT) is diagnosed, prompt evaluation and therapeutic intervention are of paramount importance for improvement in patient-important outcomes. We systematically reviewed patient-important outcomes in patients with suspected DVT, including mortality, incidence of pulmonary embolism (PE) and DVT, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, Ovid Medline, Embase for eligible studies, references lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Nine studies with 5126 patients were included for lower extremity DVT. Three studies with 500 patients were included for upper extremity DVT. Among patients with lower extremity DVT, 0.85% (95% confidence interval [CI], 0% to 2.10%) and 0% developed recurrent DVT and PE, respectively, at 3 months. Among patients with upper extremity DVT, 0.49% (95% CI, 0% to 1.16%) and 1.98% (95% CI, 0.62% to 3.33%) developed recurrent DVT and PE, respectively, at 3 months. No major bleeding events were reported for those anticoagulated, which is lower than in other systematic reviews. For both upper and lower extremity DVT, low pretest probability patients with a negative D-dimer had a comparable incidence of VTE at 3 months (∼1%) as patients with a negative ultrasound (US). At higher pretest probabilities, negative US testing with or without serial US appears to be the safer option. In this review, we summarized the outcomes of patients evaluated by various diagnostic pathways. In most instances, there was significant limitation due to small population size or lack of direct evidence of effects of using a specific pathway. This systematic review was registered at PROSPERO as CRD42018100502.

m-Trifluoromethyl-diphenyl diselenide (m-CF3-PhSe)2 modulates the hippocampal neurotoxic adaptations and abolishes a depressive-like phenotype in a short-term morphine withdrawal in mice.

The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF3-PhSe)2 elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF3-PhSe)2 developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF3-PhSe)2 attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100 mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF3-PhSe)2 (5 and 10 mg/kg, ig) or methadone (5 mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30 min after the last administration of (m-CF3-PhSe)2. Although short-term treatment with (m-CF3-PhSe)2 at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF3-PhSe)2 per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF3-PhSe)2 modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF3-PhSe)2 downregulated the proBDNF/p-75NTR/JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF3-PhSe)2 treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice.