Imidazoquinoline Derivatives as Potential Inhibitors of InhA Enzyme and Mycobacterium tuberculosis.

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein's substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth.

IL-10 predicts incident neuroinflammatory disease and proviral load dynamics in a large Brazilian cohort of people living with human T-lymphotropic virus type 1.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

The male effect associated with prostaglandins and reproductive outcomes in photo-stimulated Saanen goats during the non-breeding season.

The efficiency of combining oestrous induction via a light program (16 h of light and 8 h of darkness for 60 days, ending on Day 0 - D0) with cloprostenol administration, followed by the male effect or not, was tested in acyclic Saanen goats during the non-breeding season (June/2019 to January/2020). Initially, all animals (males and females) were submitted to the described light program; 60 days after its ending (D60), the females were divided into two groups, with (G1; n = 67) or without (G2; n = 61) a male effect from D60 to D75 after the light program. At D75, both groups received two cloprostenol doses (120 µg; intramuscular) 7.5 days apart (D75 and D82.5). Artificial insemination was performed at a specific time according to the oestrous onset (approximately 68.4 ± 1.2 h between the second cloprostenol dose and IA). Ultrasound scans were performed at different intervals to evaluate follicular dynamics and confirm pregnancy. At the first cloprostenol dose (D75), the proportion of does with at least a corpus luteum (CL), which indicates resumed cyclicity, was greater in G1 than in G2 (85.2% vs. 48.8%; p < .05), although no difference was found at the second dose (p > .05). The adjusted pregnancy rates (number of pregnant goats/oestrous goats) differed between G1 and G2 (21.7% vs. 42.0%; p < .05). G1 also showed a higher frequency of functional CL (based on blood flow and morphology) compared to G2 (96.9% vs. 66.7%; p < .05) at D116. A male effect using photo-stimulated bucks after the first cloprostenol dose increased the number of does presenting CL after buck removal, and no impairment in the pregnancy rates of multiparous does was found.

Safety and efficacy of silicone tape for indwelling urinary catheter fixation in intensive care patients-A randomized clinical trial.

BACKGROUND: Critically ill patients are more vulnerable to medical adhesive-related skin injuries (MARSI), whose prevention is a constant challenge and one of the main quality indicators of nursing care. MARSI associated with indwelling urinary catheter (IUC) fixation is a relevant adverse event, mainly because of the constant involuntary traction and high skin vulnerability of the fixation site. Silicone adhesive tape has appreciable qualities for fragile skin among the range of adhesives, leading to the inference that it reduces the risk of MARSI. AIM: To compare silicone adhesive tape for IUC fixation with acrylate tape regarding its safety and efficacy. STUDY DESIGN: This was a randomized controlled trial blinded to the patients and evaluator. Data were collected from an intensive care unit (ICU) of a tertiary university hospital in Brazil. Patients with IUC and no MARSI at the fixation site were considered eligible. The omega (Ω) fixation technique was used for IUC fixation. A total of 132 participants were enrolled and divided into two research groups: 66 patients in the intervention group (silicone tape) and 66 in the control group (acrylate tape). Outcomes were the incidence of MARSI, patient outcome in the ICU and hospital and partial, total and overall spontaneous detachment of the tapes. RESULTS: The overall incidence of MARSI was 28%, with 21% in the silicone group and 35% in the acrylate group, with no statistically significant difference (p = .121), including the severity of the lesions (p = .902). However, partial (p = .003) and overall (p < .001) detachment of the tapes were more frequent in the silicone group. CONCLUSIONS: Silicone tape is no safer than acrylate tape for IUC fixation and is less adhesively effective. RELEVANCE TO CLINICAL PRACTICE: There is no evidence to support the extensive use of silicone tape in this context.

OPRM1 and BDNF polymorphisms associated with a compensatory neurophysiologic signature in knee osteoarthritis patients.

OBJECTIVE: The present study investigated the relationship between three genetic polymorphisms of OPRM1 (rs1799971 - A118G and rs1799972 - C17T) and BDNF (rs6265 - C196T) and EEG-measured brain oscillations in Knee Osteoarthritis (KOA) patients. MATERIALS AND METHODS: We performed a cross-sectional analysis of a cohort study (DEFINE cohort), KOA arm, with 66 patients, considering demographic (age, sex, and education), clinical (pain intensity and duration), OPRM1 (rs1799971 - A118G and rs1799972 - C17T) and BDNF (rs6265 - C196T) genotypes, and electrophysiological measures. Brain oscillations relative power from Delta, Theta, Alpha, Low Alpha, High Alpha, Beta, Low Beta and High Beta oscillations were measured during resting state EEG. Multivariate regression models were used to explore the main brain oscillation predictors of the three genetic polymorphisms. RESULTS: Our findings demonstrate that Theta and Low Beta oscillations are associated with the variant allele of OPRM1-rs1799971 (A118G) on left frontal and left central regions, respectively, while Alpha brain oscillation is associated with variant genotypes (CT/TT) of BDNF-rs6265 on frontal (decrease of oscillation power) and left central (increase of oscillation power) regions. No significant model was found for OPRM1-rs1799972 (C17T) in addition to the inclusion of pain intensity as a significant predictor of this last model. CONCLUSION: One potential interpretation for these findings is that polymorphisms of OPRM1 - that is involved with endogenous pain control - lead to increased compensatory oscillatory mechanisms, characterized by increased theta oscillations. Along the same line, polymorphisms of the BDNF lead to decreased alpha oscillations in the frontal area, likely also reflecting the disruption of resting states to also compensate for the increased injury associated with knee OA. It is possible that these polymorphisms require additional brain adaption to the knee OA related injury.

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids.

A series of 25 chiral anti-cancer lipidic alkynylcarbinols (LACs) were devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting phenyl-dialkynylcarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC50 down to 40 nM for resolved eutomers. A clickable probe was used to confirm the PAC prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 short-chain dehydrogenase/reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin-proteasome system inhibition, and apoptosis. Insights into the design of LAC prodrugs specifically bioactivated by HSD17B11 vs its paralogue HSD17B13 were obtained. The HSD17B11/HSD17B13-dependent cytotoxicity of PACs was exploited to develop a cellular assay to identify specific inhibitors of these enzymes. A docking study was performed with the HSD17B11 AlphaFold model, providing a molecular basis of the SDR substrates mimicry by PACs. The safety profile of a representative PAC was established in mice.

Health-related quality of life and functionality in primary caregiver of surviving pediatric COVID-19.

Objectives: To prospectively assess health-related quality of life (HRQoL), global functionality, and disability in primary caregivers of surviving children and adolescents after COVID-19. Methods: A longitudinal observational study was carried out on primary caregivers of surviving pediatric post-COVID-19 patients (n = 51) and subjects without COVID-19 (n = 60). EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and 12-question WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) were answered for both groups. The univariate regression analysis was carried out using SPSS (v 20) and significance was established at 5%. Results: The median duration between COVID-19 diagnosis in children and adolescents and longitudinal follow-up visits was 4.4 months (0.8-10.7). The median age of children and adolescents caregivers with laboratory-confirmed COVID-19 was similar to primary caregivers of subjects without laboratory-confirmed COVID-19 [43.2 (31.6-60.9) vs. 41.5 (21.6-54.8) years, p = 0.08], as well as similar female sex (p = 1.00), level of schooling (p = 0.11), social assistance program (p = 0.28), family income/month U$ (p = 0.25) and the number of household's members in the residence (p = 0.68). The frequency of slight to extreme problems (level ≥ 2) of the pain/discomfort domain according to EQ-5D-5L score was significantly higher in the former group [74% vs. 52.5%, p = 0.03, OR = 2.57 (1.14-5.96)]. The frequency of disability according to WHODAS 2.0 total score was similar to those without disability and unknown (p = 0.79); however, with a very high disability in both groups (72.5% and 78.3%). Further analysis of primary caregivers of children and adolescents with post-COVID-19 condition (PCC) [n = 12/51 (23%)] compared to those without PCC [n = 39/51(77%)] revealed no differences between demographic data, EQ-5D-5L and WHODAS 2.0 scores in both groups (p > 0.05). Conclusion: We longitudinally demonstrated that pain/discomfort were predominantly reported in approximately 75% of primary caregiver of COVID-19 patients, with high disability in approximately three-quarters of both caregiver groups. These data emphasized the prospective and systematic caregiver burden evaluation relevance of pediatric COVID-19.

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

Fluorescence-aided identification technique using a low-cost violet flashlight and rotatory instruments for dental trauma splint removal.

BACKGROUND/AIM: Removing resin composites used for bonding dental trauma splints may result in irreversible damage to the enamel. This in vitro study evaluated the influence of additional violet illumination and different bur types on damage caused to tooth enamel. MATERIALS AND METHODS: Fifteen maxillary models with four bovine incisor teeth were prepared. All models were scanned using a laboratory scanning system (s600 ARTI; Zirkonzahn). Six experimental groups (n = 10) were generated by two study factors: lighting type (three levels), (1) low-cost (5-7 US$) violet LED flashlight (LUATEK, LT 408); (2) VALO Cordless light curing unit (Ultradent) with black lens; or (3) without additional illumination; and rotatory instrument (two levels), (1) diamond bur or (2) multifluted tungsten-carbide bur. New scanning was performed after splint removal, and the generated files were superimposed on the initial scans using Cumulus software. The light emitted by both violet light sources was characterized by using integrating sphere and beam profile. A qualitative and quantitative analysis of enamel damage and two-way ANOVA followed by Tukey's post hoc was used at an α = 0.05. RESULTS: The use of low-cost violet flashlight that emitted the violet peak light at 385 nm and VALO Cordless with black lens at 396 nm resulted in significantly lower damage to the enamel surface than those in the groups without additional violet light (p < .001). An interaction between rotatory instruments and lighting was found. When no additional violet lighting was used, the diamond bur presented higher mean and maximum depth values. CONCLUSIONS: Fluorescence lighting facilitated the removal of remnant resin composite dental trauma splints, leading to less invasive treatment. The diamond bur resulted in higher enamel damage than that affected by the multifluted bur when no violet lighting was used. A low-cost violet flashlight is a useful fluorescence-aided identification technique for removing resin composite dental trauma splints.

Effects of red and infrared laser on post extraction socket repair in rats subjected to alendronate therapy.

This study evaluated the effect of photobiomodulation therapy (PBMT) with a red or infrared laser on the repair of post extraction sockets in rats administered alendronate (ALN). Forty male rats were randomly allocated into four groups: Control Group (CTR): subcutaneous administration of saline solution throughout the experimental period; Alendronate Group (ALN): subcutaneous administration of alendronate during the entire experimental period; Alendronate/Red Laser Group (ALN/RL): administration of ALN and irradiation with a GaAlAs laser (λ 660 nm); and Alendronate/Infrared Laser Group (ALN/IRL): administration of ALN and irradiation with a GaAlAs laser (λ 830 nm). The first lower molars were extracted 60 days after the beginning of the administration of the drugs. The PBMT was applied after tooth extraction (7 sessions with intervals of 48 hours between sessions). Thirty days after tooth extraction, the animals were euthanized. Micro-CT and histometric analysis were performed to assess the bone healing and soft tissue repair of the tooth socket. The ALN group presented with more bone than the CTR; however, most of this bone was necrotic. ALN does not affect the bone microarchitecture. On the other hand, PBMT with IRL enhances the bone density due to the increase in the number and reduction in the spacing of the trabeculae. The amount of vital bone and connective tissue matrix was higher in the ALN/RL and ALN/IRL groups than in the ALN and CTR groups. PBMT enhanced the healing of the post extraction sockets in rats subjected to ALN administration. Furthermore, IRL improved the new bone microarchitecture.

Association of Mu opioid receptor (A118G) and BDNF (G196A) polymorphisms with rehabilitation-induced cortical inhibition and analgesic response in chronic osteoarthritis pain.

Background/objective: Chronic pain due to osteoarthritis (OA) is a prevalent cause of global disability. New biomarkers are needed to improve treatment allocation, and genetic polymorphisms are promising candidates. Method: We aimed to assess the association of OPRM1 (A118G and C17T) and brain-derived neurotrophic factor (BDNF [G196A]) polymorphisms with pain-related outcomes and motor cortex excitability metrics (measured by transcranial magnetic stimulation) in 113 knee OA patients with chronic pain. We performed adjusted multivariate regression analyses to compare carriers versus non-carriers in terms of clinical and neurophysiological characteristics at baseline, and treatment response (pain reduction and increased cortical inhibitory tonus) after rehabilitation. Results: Compared to non-carriers, participants with polymorphisms on both OPRM1 (A118G) and BDNF (G196A) genes were less likely to improve pain after rehabilitation (85 and 72% fewer odds of improvement, respectively). Likewise, both carriers of OPRM1 polymorphisms (A118G and C17T) were also less likely to improve cortical inhibition (short intracortical inhibition [SICI], and intracortical facilitation [ICF], respectively). While pain and cortical inhibition improvement did not correlate in the total sample, the presence of OPRM1 (A118G) and BDNF (G196A) polymorphisms moderated this relationship. Conclusions: These results underscore the promising role of combining genetic and neurophysiological markers to endotype the treatment response in this population.

Circulating sTREM-1 as a predictive biomarker of pediatric multisystemic inflammatory syndrome (MIS-C).

The exacerbation of the inflammatory response caused by SARS-CoV-2 in adults promotes the production of soluble mediators that could act as diagnostic and prognostic biomarkers for COVID-19. Among the potential biomarkers, the soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) has been described as a predictor of inflammation severity. The aim was to evaluate sTREM-1 and cytokine serum concentrations in pediatric patients during the acute and convalescent phases of COVID-19. This was a prospective study that included 53 children/adolescents with acute COVID-19 (Acute-CoV group); 54 who recovered from COVID-19 (Post-CoV group) and 54 controls (Control group). Preexisting chronic conditions were present in the three groups, which were defined as follows: immunological diseases, neurological disorders, and renal and hepatic failures. The three groups were matched by age, sex, and similar preexisting chronic conditions. No differences in sTREM-1 levels were detected among the groups or when the groups were separately analyzed by preexisting chronic conditions. However, sTREM-1 analysis in the seven multisystemic inflammatory syndrome children (MIS-C) within the Acute-Cov group showed that sTREM-1 concentrations were higher in MIS-C vs non-MIS-C acute patients. Then, the receiver operating curve analysis (ROC) performed with MIS-C acute patients revealed a significant AUC of 0.870, and the sTREM-1 cutoff value of > 5781 pg/mL yielded a sensitivity of 71.4 % and a specificity of 91.3 % for disease severity, and patients with sTREM-1 levels above this cutoff presented an elevated risk for MIS-C development in 22.85-fold (OR = 22.85 [95 % CI 1.64-317.5], p = 0.02). The cytokine analyses in the acute phase revealed that IL-6, IL-8, and IL-10 concentrations were elevated regardless of whether the patient developed MIS-C, and those levels decreased in the convalescent phase, even when compared with controls. Spearman correlation analysis generated positive indexes between sTREM-1 and IL-12 and TNF-α concentrations, only within the Acute-CoV group. Our findings revealed that sTREM-1 in pediatric patients has good predictive accuracy as an early screening tool for surveillance of MIS-C cases, even in patients with chronic underlying conditions.

Ações educativas na melhoria da comunicação entre profissionais de saúde: revisão integrativa / Educational actions to improve communication among health professionals: integrative review / Acciones educativas para mejorar la comunicación entre los profesionales de la salud: revisión inte-gradora

Objetivo: Mapear as ações educativas para a melhoria na comunicação entre profissionais de saúde. Método: Revisão integrativa entre junho e agosto de 2021. Incluídos artigos com texto completo, publicados entre 2016 e 2021, em português, inglês e espanhol. Excluídos resumos, editoriais, dissertações, teses e artigos que não incluíram a temática selecionada. Utilizou-se as bases de dados: Biblioteca Virtual em Saúde, Literatura Latino-americana e do Caribe em Ciências da Saúde, PubMed, Scientific Electronic Library Online, através dos descritores "Sistemas de comunicação no hospital", "Educação", "Pessoal de saúde". associados através dos operadores booleanos "AND" ou "OR". Os artigos foram organizados e analisados por similaridade de conteúdo. Resultados: Foram analisados 2 artigos e identificou-se duas categorias: "Simulação e desenvolvimento de habilidade de comunicação interdisciplinar" e "Desenvolvimento de programa eletrônico envolvendo a comunicação entre profissionais de saúde". Conclusão: Observou-se escassez de pesquisas relacionadas à temática. Sugere-se que novas investigações sejam realizadas no que diz respeito à comunicação entre profissionais (AU).

Objective: To map educational actions to improve communication between health professionals. Method: Integrative review between June and August 2021. Included full-text articles, published between 2016 and 2021, in Portuguese, English and Spanish. Abstracts, editorials, dissertations, theses and articles that did not include the selected theme were excluded. The following databases were used: Virtual Health Library, Latin American and Caribbean Health Sciences Literature, PubMed, Scientific Electronic Library Online, through the descriptors "Communication systems in the hospital", "Education", "Health personnel". associated through boolean operators "AND" or "OR". The articles were organized and analyzed by content similarity. Results: Two articles were analyzed and two categories were identified: "Simulation and development of interdisciplinary communication skills" and "Development of an electronic program involving communication between health professionals". Conclusion: There was a scarcity of research related to the theme. It is suggested that further investigations be carried out with regard to communication between professionals (AU).

Objetivo: Mapear acciones educativas para mejorar la comunicación entre los profesionales de la salud. Método: Revisión integradora entre junio y agosto de 2021. Incluye artículos de texto completo, publicados entre 2016 y 2021, en portugués, inglés y español. Se excluyeron resúmenes, editoriales, disertaciones, tesis y artículos que no incluyeran el tema seleccionado. Se utilizaron las siguientes bases de datos: Biblioteca Virtual en Salud, Literatura Latinoamericana y del Caribe en Ciencias de la Salud, PubMed, Biblioteca Científica Electrónica en Línea, a través de los descriptores "Sistemas de comunicación en el hospital", "Educación", "Personal de salud". asociados a través de operadores booleanos "AND" o "OR". Los artículos fueron organizados y analizados por similitud de contenido. Resultados: Se analizaron dos artículos y se identificaron dos categorías: "Simulación y desarrollo de habilidades de comunicación interdisciplinarias" y "Desarrollo de un programa electrónico que involucra la comunicación entre profesionales de la salud". Conclusión: Hubo escasez de investigaciones relacionadas con el tema. Se sugiere que se lleven a cabo más investigaciones con respecto a la comunicación entre profesionales (AU).

Effects of red and infrared laser on post extraction socket repair in rats subjected to alendronate therapy

Abstract This study evaluated the effect of photobiomodulation therapy (PBMT) with a red or infrared laser on the repair of post extraction sockets in rats administered alendronate (ALN). Forty male rats were randomly allocated into four groups: Control Group (CTR): subcutaneous administration of saline solution throughout the experimental period; Alendronate Group (ALN): subcutaneous administration of alendronate during the entire experimental period; Alendronate/Red Laser Group (ALN/RL): administration of ALN and irradiation with a GaAlAs laser (λ 660 nm); and Alendronate/Infrared Laser Group (ALN/IRL): administration of ALN and irradiation with a GaAlAs laser (λ 830 nm). The first lower molars were extracted 60 days after the beginning of the administration of the drugs. The PBMT was applied after tooth extraction (7 sessions with intervals of 48 hours between sessions). Thirty days after tooth extraction, the animals were euthanized. Micro-CT and histometric analysis were performed to assess the bone healing and soft tissue repair of the tooth socket. The ALN group presented with more bone than the CTR; however, most of this bone was necrotic. ALN does not affect the bone microarchitecture. On the other hand, PBMT with IRL enhances the bone density due to the increase in the number and reduction in the spacing of the trabeculae. The amount of vital bone and connective tissue matrix was higher in the ALN/RL and ALN/IRL groups than in the ALN and CTR groups. PBMT enhanced the healing of the post extraction sockets in rats subjected to ALN administration. Furthermore, IRL improved the new bone microarchitecture.

Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Motor event-related synchronization as an inhibitory biomarker of pain severity, sensitivity, and chronicity in patients with knee osteoarthritis.

OBJECTIVE: The study aimed to examine the clinical and neurophysiological predictors of motor event-related desynchronization (ERD) and synchronization (ERS) in patients with chronic pain due to knee osteoarthritis (KOA). METHODS: We performed a cross-sectional analysis of our cohort study (DEFINE cohort), KOA arm, with 71 patients, including demographic, functionality, genetic and neurophysiological measures. ERD/ERS was evaluated during hand motor tasks (motor execution, active and passive observation, and imagery). Multivariate regression models were used to explore predictors of ERD/ERS. RESULTS: Although we found an altered ERD/ERS pattern during motor execution and active observation, the ERS pattern could only be clearly differentiated after passive observation.`. We found no predictors of ERD (excitatory biomarker). For ERS (inhibitory biomarker), our results showed that the main predictors differ across EEG frequency bands. Considering pain measures, we found that visual analogue scale (VAS, right knee) and chronicity of pain negatively predict low beta and high beta ERS, respectively. Pain threshold was positively correlated with alpha ERS, while 36-Item Short Form Survey (SF-36) emotional domain positively predicted beta ERS. Regarding transcranial magnetic stimulation (TMS) markers, intracortical inhibition (ICF) negatively predicted beta and low beta ERS, and left hemisphere cortical silent period (CSP) negatively predicted low beta ERS. CONCLUSION: Considering that higher power of ERS indicates a stronger cortical organization and inhibitory drive, our results show that limitation of activities due to emotional factors, lower pain threshold, higher VAS pain, and longer duration of pain are associated with lower ERS power (in alpha and beta frequencies), thus indicating a lower inhibitory drive. In the same direction, a lower inhibitory drive as indicated by higher ERS power is associated with higher ICF amplitude. Although there was a negative association between ERS and CSP, this may indicate that ICF values are adjusting CSP results. Our findings support the idea that a less organized cortical response as indicated by changes to the ERS is associated with higher pain correlates in subjects with KOA.

Validação do instrumento de cuidado do enfermeiro ao paciente crítico com cateter venoso central / Validation of the nurse's care instrument for the critical patient with a central venous catheter / Validación de un instrumento para la atención de enfermería a pacientes críticos con catéteres venosos centrales

Objetivo: Validar o conteúdo do instrumento de cuidado do enfermeiro ao paciente com cateter venoso central, internado na unidade de terapia intensiva. Métodos: Estudo quantitativo, conduzido em duas etapas: análise teórica por sete enfermeiros especialistas, dos itens do instrumento construído anteriormente e análise estatística a partir do Índice de Validade de Conteúdo e o coeficiente Alpha de Cronbach. Resultados: Após avaliação dos especialistas, o instrumento compôs- se por 36 itens e quatro domínios. Todos os itens apresentaram índice de validade de conteúdo superior a 0,78, com concordância de 0,85 a 1,00 nas avaliações. O índice de validade de conteúdo médio dos domínios e do instrumento foi maior que 0,90. Os itens dos domínios apresentaram consistência interna satisfatória. Conclusão: O instrumento de cuidado do enfermeiro apresentou conteúdo validado e confiável, sendo, portanto, seguro e de qualidade para cuidados com o paciente crítico com cateter venoso central.

Objective: To validate the content of the nurse's care instrument for patient with a central venous catheter in the intensive care unit. Methods: Quantitative study, conducted in two stages: theoretical analysis by seven specialist nurses of the instrument items previously developed and statistical analysis based on the Content Validity Index and Cronbach's Alpha coefficient. Results: After expert evaluation, the instrument consisted of 36 items and four domains. All items had a content validity index greater than 0.78, with an agreement between 0.85 and 1.00 in the evaluations. The mean content validity index of the domains and the instrument was greater than 0.90. The domain items showed satisfactory internal consistency. Conclusion: The nurse's care instrument presented validated and reliable content, being, therefore, safe and of quality for the care of critically ill patients with central venous catheters.

Objetivo: Validar el contenido del instrumento de atención de la enfermera al paciente con catéter venoso central, ingresado en la unidad de cuidados intensivos. Métodos: Estudio cuantitativo, conducido en dos etapas: análisis teórico por parte de siete enfermeros especialistas, de los ítems del instrumento construido anteriormente y análisis estadístico a partir del Índice de Validez de Conteúdo y el coeficiente Alpha de Cronbach. Resultados: Tras la evaluación de los expertos, el instrumento quedó compuesto por 36 ítems y cuatro dominios. Todos los ítems tuvieron un índice de validez de contenido superior a 0,78, con un acuerdo entre 0,85 y 1,00 en las evaluaciones. El índice medio de validez de contenido de los dominios y del instrumento fue superior a 0,90. Los ítems de los dominios mostraron una consistencia interna satisfactoria. Conclusión: El instrumento de cuidado del enfermero presentó un contenido validado y fiable, siendo, además, seguro y de calidad para el cuidado del paciente crítico con catéter venoso central.

The copy number variation of GSTM1 as a promising prognostic factor of oral squamous cell carcinoma.

OBJECTIVE: The aim of this study was to investigate whether the copy number variation (CNV) of GSTM1 and GSTT1 is related to the occurrence of oral squamous cell carcinoma (OSCC) relapses, along the overall and progression-free survival of patients. STUDY DESIGN: A total of 234 OSCC patients were recruited from the Heliópolis hospital and they were distributed among 4 groups according to the occurrence of OSCC relapses. Fisher exact test, odds ratio (OR), and 95% CI were determined to investigate the chances of OSCC progression. The overall and progression-free survival were analyzed by the Kaplan-Meier and Cox regression methods. RESULTS: The CNV of GSTM1 analysis showed that one copy of the gene was associated with reduced chances of OSCC recurrences (OR 0.45; 95% CI 0.25-0.81) and decreased the risk of tumor progression (HR 0.50; 95% CI 0.33-0.75). Furthermore, one copy of GSTM1 was related to a better overall survival rate (HR 0.63; 95% CI 0.0.44-0.91). Regarding the CNV of GSTT1, no copies were associated with the chances of OSCC relapses, the overall survival, or the progression-free survival. CONCLUSIONS: The CNV of GSTM1 may be applied to predict OSCC relapses and aid the treatment management, which might improve the survival rates of patients.

Many hands make light work: CNV of GSTM1 effect on the oral carcinoma risk.

BACKGROUND: Genetic alterations of oral squamous cell carcinoma (OSCC) allow the understanding of the oral carcinogenesis and the identification of molecular biomarkers that aid the early diagnosis of the disease. The copy number variation (CNV) of GSTM1 and GSTT1 are promising targets because these two genes codify enzymes that perform the inactivation of tobacco carcinogens, which are the main risk factor of OSCC. However, the different levels of - detoxification mechanism in relation to each copy of the genes are unknown. Therefore, this study aimed to investigate the possible association of the CNV of GSTM1 and GSTT1 with the risk of development of OSCC. METHODS: A total of 234 OSCC patients and 422 patients without any cancer diagnoses were recruited from Heliópolis Hospital from 2000 to 2011. The CNV was determined by TaqMan real-time PCR and the CopyCaller software. Odds ratio (OR) and 95% confidence interval (95% CI) values were calculated by Multiple Logistic Regression. RESULTS: Most OSCC patients reported they continued smoking high amounts of cigarettes despite the tumor diagnosis. The CNV of GSTM1 varied from zero to two copies and the analysis revealed that two copies of GSTM1 decreased by 53% the OSCC risk (OR 0.47; 95% CI 0.24-0.92) and the risk of the tumor was modified according to the interaction of the CNV of GSTM1 and the cigarette smoking consumption, which for the amount of 40 packs-year of cigarettes the OSCC risk diminished progressively according to the increase of copies of GSTM1. Although the GSTT1 gene varied from zero to three copies, none of them were associated with the tumor risk. CONCLUSION: The findings suggest that the CNV of GSTM1 might be applied as a tool for the surveillance of patients and the early detection of OSCC.

Keeping It Real: Infection Prevention and Control Problems and Solutions in Low- and Middle-income Countries.

Infection prevention challenges are ubiquitous in healthcare, but some are unique to or more prevalent in low-and middle-income country settings. Despite limited resources, innovative and committed paediatric healthcare providers and infection preventionists have found creative solutions to address the very real and pressing risks their patients face every day. We gathered examples of infection prevention and control challenges faced by clinicians in resource-limited healthcare facilities, and the real-world infection prevention and control solutions they implemented, with the goal of learning broader lessons applicable to low-and middle-income countrie.