Concordance rate between oligoclonal bands and the Kappa index in patients with suspected multiple sclerosis (MS).

BACKGROUND: Oligoclonal bands (OCBs) and Kappa free light chains (FLCs) in the cerebrospinal fluid (CSF) are sensitive markers of intrathecal immunoglobulin (Ig)G synthesis in patients with multiple sclerosis. OBJECTIVE: To evaluate the concordance rate between OCBCs and the Kappa index (KI) in patients with suspected multiple sclerosis (MS). METHODS: Patients with suspected MS were referred to a specialized CSF laboratory as part of their diagnostic investigation. Paired CSF and serum samples were collected and submitted to detection of OCBs and determination of the KI. Positive and negative results were determined with both methods, and the percentage of agreement between them was established. RESULTS: In total, 171 serum and CSF samples from 171 patients were included in the analysis. The mean age of the patients was of 40 ± 14.2 years; 18.9% of them were male, and 81.1% were female. The OCBs and KI presented concordant results in 161 (94.2%) samples: in 74 (43.3%), both were positive, and in 87 (50.9%), both were negative. In 10 cases, the results were discrepant: KI positive/OCB negative in 8 and OCB positive/KI negative in 2 cases. CONCLUSION: The KI and OCBs presented high concordance level. Currently, the detection of OCBs in the CSF is the standard method for MS diagnosis, but it is time-consuming, and its visual interpretation can be difficult. The results suggest that the KI is a good alternative for the detection of intrathecal immunoproduction in cases of suspected MS.

ANTECEDENTES: Bandas oligoclonais (BOCs) e cadeias leves de imunoglobulina (free light chains, FLCs, em inglês) Kappa no líquido cefalorraquidiano (LCR) são marcadores sensíveis da síntese intratecal de imunoglobulina (Ig)G em pacientes com esclerose múltipla (EM). OBJETIVO: Avaliar a taxa de concordância entre BOCs e o índice Kappa (IK) em pacientes com suspeita de EM. MéTODOS: Pacientes com suspeita de EM foram encaminhados a um laboratório especializado em LCR como parte de sua investigação diagnóstica. Amostras pareadas de LCR e soro foram coletadas e investigadas quanto à presença de BOCs e submetidas à determinação do IK. Resultados positivos e negativos foram determinados com ambos os métodos, e estabeleceu-se o percentual de concordância entre eles. RESULTADOS: Ao todo, 171 amostras de soro e LCR de 171 pacientes foram incluídas na análise. A média de idade dos pacientes foi de 40 ± 14,2 anos; 18,9% deles eram do sexo masculino, e 81,1%, do sexo feminino. Resultados concordantes entre as BOCs e o IK foram observados em 161 (94,2%) amostras: em 74 (43,3%), ambos foram positivos, e em 87 (50,9%), ambos foram negativos. Em 10 casos, os resultados foram discrepantes: IK positivo/BOC negativo em 8, e BOC positivo/IK negativo em 2. CONCLUSãO: Observou-se alto nível de concordância entre o IK e as BOCs. A detecção de BOCs no LCR é atualmente o método padrão para o diagnóstico de EM, mas é demorado, e sua interpretação visual pode ser difícil. Os resultados sugerem que o IK pode ser uma alternativa para a detecção de imunoprodução intratecal em casos de suspeita de EM.

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis.

The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.

Steroid immune responsive gene regulation in Mycobacterium tuberculosis infection in vitro.

Tuberculosis (TB) is an infectious disease displaying a multifactorial pathology. The immunomodulatory role attributed to steroid hormones, such as vitamin D3 (VD3) and 17ß-estradiol (E2), highlighted the importance of these hormones against Mycobacterium tuberculosis (Mtb) infection. In order to understand their influence upon gene expression of immune and inflammatory responsive genes against Mtb we tested it in vitro using peripheral blood mononuclear cells (PBMCs). Cells were pretreated with VD3 (50 ng/mL) or E2 (100 nM/mL) and co-cultured with H37Rv Mtb or stimulated with lipopolysaccharide from Escherichia coli (LPS). After 24 h and 72 h of co-culture the Mtb viability in macrophages test was performed, as well the total RNA isolation for gene expression analysis by RT-qPCR of the following target genes: NLRP3, DC-SIGN, IL-1ß, and IL-10. We also measured IL-10, TNF, IFN-γ, IL-4, IL-6, and IL-2 supernatant levels. As the main results, we found that VD3 and E2 downregulated the expression of inflammatory genes NLRP3, IL-1ß, and IL-10 expression in Mtb co-cultured cells. Finally, VD3 treatment increased the release of the cytokine IFN-γ in Mtb-infected cells, while E2 treatment inhibited the release of IL-10, TNF, IFN-γ, and IL-6. Therefore, we report an immunogenetic influence of VD3 and E2 upon Mtb co-culture.

The impact of echocardiographic indexation to evaluate cardiac reverse remodeling throughout pregnancy and postpartum.

INTRODUCTION AND OBJECTIVES: Echocardiography guidelines suggest normalizing left ventricular (LV) volumes and mass (LVM) to body size. During pregnancy, continuous weight variation impacts on body surface area (BSA) calculation, limiting the longitudinal analysis of cardiac remodeling (CR) and reverse remodeling (RR) variables. Our aim was to identify the most common indexing methodologies in the literature on pregnant populations through a systematic review; and, to compare four scaling methods: (i) none (absolute values); (ii) indexing to the BSA before pregnancy; (iii) allomeric indexing; and (iv) indexing to BSA measured at the same day of cardiac assessment, using an illustrative example. METHODS: We performed a systematic review of CR and RR during pregnancy and post-partum, using two databases. We included studies reporting longitudinal echocardiographic analysis of cardiac chamber volumes in humans. We used a prospective cohort study of healthy pregnant women who underwent four echocardiographic evaluations during pregnancy and postpartum, as an illustrative example. RESULTS: Twenty-seven studies were included, most studies indexed to BSA measured at each evaluation moment (n=21). Within-subjects design was the most reported to analyse longitudinal data (n=17). Indexation to the pre-pregnancy BSA or application of allometric indexes revealed a higher effect than BSA measured at each evaluation and an equal effect to not indexing using within-subjects design. The within-subjects designs also revealed a higher effect size value than the between-subjects design for longitudinal analysis of LVM adaptations during pregnancy and postpartum. CONCLUSION(S): This study concludes that indexation methods do not impact the clinical interpretation of longitudinal echocardiographic assessment but highlights the need to harmonize normalization procedures during pregnancy.

BubR1 and cyclin B1 immunoexpression in pleomorphic adenoma and polymorphous adenocarcinoma of minor salivary glands.

The immunoexpression of BubR1 and cyclin B1 in pleomorphic adenoma (PA) and polymorphic adenocarcinoma (PAC) in minor salivary glands is poorly studied. Thus, a retrospective and observational study was performed to provide a better understanding of the role and immunopositivity patterns of these proteins in these lesions. Sixteen cases of PA and 16 cases of PAC were selected. Parenchyma cells were submitted to quantitative immunohistochemical analysis through the labeling index. Cytoplasmic immunoexpression of BubR1 was observed in neoplastic cells from all analyzed PA and PAC cases. All PA cases and 93.7% of PAC exhibited nuclear immunoexpression of BubR1. Higher cytoplasmic and nuclear immunoexpression of BubR1 was observed in PAC (p = 0.001 and p = 0.122, respectively). Cytoplasmic immunoexpression of cyclin B1 was observed in all cases of PA and PAC, with a higher labeling index in the latter (p < 0.001). There was a significant positive correlation between nuclear and cytoplasmic BubR1 immunoexpressions (p < 0.001) in PA and a significant negative correlation between BubR1 and cyclin B1 cytoplasmic immunoexpressions (p = 0.014) in PAC. The higher cytoplasmic and nuclear immunoexpression of BubR1 in PACs suggests the continuous maintenance of neoplastic cells in the cell cycle and migration. Higher immunoexpression of cyclin B1 supports this lesion's enhanced proliferative and migration ability.

Transmission of Xanthomonas albilineans by the spittlebug, Mahanarva fimbriolata (Hemiptera: Cercopidae), in Brazil: first report of an insect vector for the causal agent of sugarcane leaf scald.

Leaf scald is a destructive sugarcane disease caused by the bacterium Xanthomonas albilineans (Ashby) Dowson. This pathogen presents the gene cluster SPI-1 T3SS, a conserved feature in pathogens vectored by animals. In this study, the competence of Mahanarva fimbriolata (Stål), a spittlebug commonly found in sugarcane fields in Brazil, was evaluated for the transmission of X. albilineans. Artificial probing assays were conducted to investigate the ability of M. fimbriolata adults to acquire X. albilineans from artificial diets containing the pathogen with subsequent inoculation of X. albilineans into pathogen-free diets. Plant probing assays with M. fimbriolata adults were conducted to evaluate the acquisition of X. albilineans from diseased source plants and subsequent inoculation of healthy recipient sugarcane plants. The presence of X. albilineans DNA in saliva/diet mixtures of the artificial probing assays and both insects and plants of the plant probing assays were checked using TaqMan assays. The artificial probing assays showed that M. fimbriolata adults were able to acquire and inoculate X. albilineans in diets. Plant probing assays confirmed the competence of M. fimbriolata to transmit X. albilineans to sugarcane. Over the entire experiment, 42% of the insects had acquired the pathogen and successful inoculation of the pathogen occurred in 18% of the recipient-susceptible sugarcane plants at 72 or 96 h of inoculation access period. Assays evidenced the vector competence of M. fimbriolata for transmission of X. albilineans, opening new pathways for investigating the biology and the economic impacts of the interaction between X. albilineans and M. fimbriolata.

Effects of ENSO events on the intensity, seasonality, and diversity of reproductive phenology of Miconia (Melastomataceae) species in tropical rainforest.

We evaluated the phenology and reproductive phenological diversity of three sympatric species of Miconia in a gallery forest in the Chapada Diamantina mountains, Bahia, Brazil. The reproductive phenophases (bud, flower, immature fruit, and mature fruit) of M. alborufescens (N=38), M. holosericea (N=46), and M. prasina (N=44) were evaluated monthly, between June/2008 and June/2015. The Fournier index was used to assess the intensities of the reproductive phenophases; synchrony and seasonality were analyzed using circular statistics and the Rayleigh (Z) test. The Frideman and Wilcoxon tests were used to verify interannual variations in phenological patterns. Reproductive phenological diversity was measured by calculating the Shannon-Wiener index; ANOVA tested possible differences in the means of diversity among the different years. The reproductive phenophases of the studied Miconia species occurred sequentially (M. alborufescens, then M. holoserica, followed by M. prasina), in the transition between the dry and rainy seasons, with little overlap between them. In general, the species showed seasonal and synchronic phenological patterns, with some variations that coincided with El Niño and/or La Niña events, e.g., demonstrating changes in the periodicity, synchrony, and intensity of their phenophases. The intensity of fruiting, for example, showed increases during La Niña years. Reproductive phenological diversity appears to respond to climate changes resulting from El Niño events and periods of prolonged drought, with high Shannon-Wiener index values. The results also suggest that the effects of global climatic phenomena (El Niño and La Niña) that alter regional climatic seasonality can also cause variations in the reproductive phenological rhythms of the Miconia species studied.

Preliminary Insights of Brazilian Snake Venom Metalloproteomics.

Snakebite envenoming is one of the most significantly neglected tropical diseases in the world. The lack of diagnosis/prognosis methods for snakebite is one of our motivations to develop innovative technological solutions for Brazilian health. The objective of this work was to evaluate the protein and metallic ion composition of Crotalus durissus terrificus, Bothrops jararaca, B. alternatus, B. jararacussu, B. moojeni, B. pauloensis, and Lachesis muta muta snake venoms. Brazilian snake venoms were subjected to the shotgun proteomic approach using mass spectrometry, and metal ion analysis was performed by atomic spectrometry. Shotgun proteomics has shown three abundant toxin classes (PLA2, serine proteases, and metalloproteinases) in all snake venoms, and metallic ions analysis has evidenced that the Cu2+ ion is present exclusively in the L. m. muta venom; Ca2+ and Mg2+ ions have shown a statistical difference between the species of Bothrops and Crotalus genus, whereas the Zn2+ ion presented a statistical difference among all species studied in this work. In addition, Mg2+ ions have shown 42 times more in the C. d. terrificus venom when compared to the average concentration in the other genera. Though metal ions are a minor fraction of snake venoms, several venom toxins depend on them. We believe that these non-protein fractions are capable of assisting in the development of unprecedented diagnostic devices for Brazilian snakebites.

Phytochemical prospection, hemagglutinating and insecticidal activity of saline extracts from the seeds of Tamboril (Enterolobium contortisiliquum) Vell. Morong (Fabaceae) on Aedes aegypti (Diptera: Culicidae).

This study evaluated the insecticidal activity of crude extracts from Enterolobium contortisiliquum (Vell.) seeds on eggs and larvae of A. aegypti, and also verified the phytochemical profile and the presence of lectins in the extract. The 0.15 M NaCl saline solution was used as the extracting substance. For tests with eggs and larvae, the crude extract was used in its raw form (RCE) and boiled at 100º C for 5 min (BCE). Concentrations of 4.68; 9.37; 18.75; 28.13; 37.13 and 46.89 mg/mL, with distilled water as a negative control. Assays were performed in triplicate. The results were subjected to analysis of variance, Tukey's test and Log-Probit analysis to determine LC50 and LC90. BCE showed better results on eggs than RCE, managing to prevent the hatching of larvae in 81.66% ± 10.40 of treated eggs, at a concentration of 46.89 mg/mL. The LC50 and LC90 were set at 35.95 and 52.67 mg/mL, respectively. In tests with larvae, concentrations of 46.89 and 37.13 mg/mL, for RCE and BCE, caused 100% mortality in 24 hours of exposure. Larval mortality at the other concentrations increased with exposure time extending to 48 h. RCE, at 48 h exposure is the most promising extract on larvae (E = 72.77%, LC90 = 10.86 mg/mL). In RCE, the presence of lectins and secondary metabolites: flavonoids, xanthones and phenols, were detected. The results demonstrate the potential of E. contortisiliquum seed extracts with ovicidal and larvicidal action on A. aegypti.

COVID-19 vaccine effectiveness in children by age groups. A population-based study in Galicia, Spain.

BACKGROUND: Studies on vaccine effectiveness (VE) against COVID-19 in the pediatric population are outgoing. We aimed to quantify VE against SARS-CoV-2 in two pediatric age groups, 5-11 and 12-17-year-old, while considering vaccine type, SARS-CoV-2 variant, and duration of protection. METHODS: A population-based test-negative control study was undertaken in Galicia, Spain. Children 5-11-year-old received the Comirnaty® (Pfizer, US) vaccine, while those aged 12-17-year-old received the Comirnaty® (Pfizer, US) or SpikeVax® (ModernaTX, Inc) vaccine. Participants were categorized into unvaccinated (0 doses or one dose with <14 days since vaccination), partially vaccinated (only one dose with ≥14 days, or two doses with <14 days after the second dose administration), and fully vaccinated (two doses with ≥14 days after the second injection). Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were estimated using multiple logistic regression models. VE was calculated as (1-OR) * 100. Stratified and sensitivity analyses were performed. RESULTS: In the fully vaccinated 5-11-year-old children, VE against the Omicron variant was 44.1% (95% CI: 38.2%-49.4%). In the fully vaccinated 12-17-year-old individuals, VE was 83.4% (95% CI: 81.2%-85.3%) against Delta and 74.8% (95% CI: 58.5%-84.9%) against Omicron. Comirnaty® and SpikeVax® vaccines showed a similar magnitude of VE against Delta [Comirnaty® VE: 81.9% (95% CI: 79.3%-84.1%) and SpikeVax® VE: 85.3% (95% CI: 81.9%-88.1%)]. Comirnaty® (Pfizer, US; VE: 79.7%; 95% CI: 50.7%-92.4%) showed a slightly higher magnitude of protection against Omicron than SpikeVax® (ModernaTX, Inc), yet with an overlapping CI (VE: 74.3%; 95% CI: 56.6%-84.9%). VE was maintained in all age subgroups in both pediatric populations, but it declined over time. CONCLUSIONS: In Galicia, mRNA VE was moderate against SARS-CoV-2 infections in the 5-11-year-old populations, but high in older children. VE declined over time, suggesting a potential need for booster dose schedules.

Hypertonic glucose in the treatment of low back pain: A randomized clinical trial.

BACKGROUND: Chronic low back pain (LBP) is defined as pain lasting longer than 3 months and is one of the conditions with the most significant social impact. Treatment is complex and includes proliferative agents used in prolotherapy. The mechanism is not known, but osmotic agents (hypertonic solutions of dextrose or glucose) cause cellular rupture and an inflammatory response that releases cytokines and growth factors that lead to scarring and reinnervation. METHODS: Patients with chronic LBP (>12 weeks) who were non-traumatic and unresponsive to at least 1 month of physical therapy were selected. All patients were followed up at a return visit at 1, 3, and 6 months for pain assessment using validated pain questionnaires and scales. RESULTS: Nineteen patients were included in the conservative group and 19 in the glucose group, with the majority being women (57.9%). The patients were between 47 and 59 years of age (39.5%), mixed race (76.33%), married or in a committed relationship (73.7%), and had completed the study for 5.2 years. Overall mean body mass index was 27.3 ± 4.4 kg/m 2 and was higher in the conservative group (28.0 ± 4.7 kg/m 2 ). The groups showed differences in Visual Analog Scale scores, with median and amplitude values close to each other between the time points evaluated and increasing values in the glucose group, which had significantly higher values for this scale at the third evaluation ( P = .031). When comparing the Rolland-Morris scale scores between the groups, there was a significant difference only in the 3-m assessment ( P = .021). In the follow-up assessment, both groups showed significant improvement between T0 and the other assessment time points ( P < .05) in all evaluations. CONCLUSION: Both groups significantly improved on the evaluated scales during follow-up. Overall, no effects were attributable to the glucose components or the prolotherapy protocol.

The role of galectin-3 in patients with permanent and paroxysmal Atrial Fibrillation and echocardiographic parameters of left atrial fibrosis.

BACKGROUND: Biochemical markers and imaging tests have been used with the aim of stratifying the risk and detecting atrial fibrosis. Speckle-tracking echocardiography (STE) is used for the detection of atrial fibrosis and Gal-3 provides an important prognostic value. The objective of the study was to assess the association between atrial fibrosis markers and serum levels, genetic polymorphisms and genic expression of galectin-3. METHODS: 206 patients with permanent AF and 70 patients with paroxysmal AF were included in the study. Real time PCR (TaqMan) system was used to study SNPs rs4652 and 4644 of the gene LGALS3. Serum levels of Gal-3 were determined by ELISA and STE was performed to assess fibrosis. RESULTS: Mean age of individuals with permanent AF was 66.56 ± 12 years. As for the echocardiography results, those patients showed an decrease in the following parameters peak atrial longitudinal strain (PALS) (p = 0.002) when compared to the same parameters from the paroxysmal AF group of patients. There was a correlation between serum levels of Gal-3 and PALS in the group of patients with permanent AF; the lower the levels of gal-3, the lower the LA strain (r = 0.24; p = 0.01). CONCLUSIONS: Echocardiographic findings showed association with the groups, and with serum levels of Gal-3 in patients with permanent AF. The distribution of allelic and genotypic frequencies, and of the haplotypes of polymorphism LGALS3 rs4652 and rs4644 did not present statistical variation, which suggests that those SNPs are not associated with the AF clinical forms (permanent and paroxysmal).

Use of bedside echocardiography in the care of critically ill patients - a joint consensus document of the Associação de Medicina Intensiva Brasileira, Associação Brasileira de Medicina de Emergência, and Sociedade Brasileira de Medicina Hospitalar. Part 1 - Competence in bedside echocardiography.

The use of echocardiography by physicians who are not echocardiographers has become common throughout the world across highly diverse settings where the care of acutely ill patients is provided. Echocardiographic evaluation performed in a point-of-care manner can provide relevant information regarding the mechanism of causes of shock, for example, increasing the rates of correct diagnosis and allowing for faster informed decision-making than through evaluation methods. Considering that the accurate diagnosis of life-threatening situations is essential for professionals working with acutely ill patients, several international associations recommend that physicians responsible for critically ill patients acquire and develop the ability to perform bedside ultrasound examinations, including echocardiographic examinations. However, there is no consensus in the literature regarding which specific applications should be included in the list of skills for nonechocardiographer physicians. Taking into account the multiplicity of applications of echocardiography in different scenarios related to acutely ill patients; the differences in the published protocols, with regard to both the teaching methodology and competence verification; and the heterogeneity of training among highly diverse specialties responsible for their care at different levels, this consensus document aimed to reflect the position of representatives of related Brazilian medical societies on the subject and may thus serve as a starting point both for standardization among different specialties and for the transmission of knowledge and verification of the corresponding competencies.

Measuring the clustering effect of the SARS-CoV-2 transmission in a school population: a cross-sectional study in a high incidence region.

Since the beginning of the pandemic, there has been a great deal of controversy regarding the role of schools in the spread of SARS-CoV-2 infection, and the relative contribution of students, teachers, and others. To quantify the clustering effect of SARS-CoV-2 infection within classes and schools considering the seroprevalence of specific antibodies among students and school staff (teachers and non-teachers) evaluated in schools located in the Northern region of Portugal. 1517 individuals (1307 students and 210 school staff) from 4 public and 2 private schools, comprising daycare to secondary levels, were evaluated. A rapid point-of-care test for SARS-CoV-2 specific IgM and IgG antibodies was performed and a questionnaire was completed providing sociodemographic and clinical information. We calculated the seroprevalence of IgM and IgG antibodies and estimated the Median Odds Ratio (OR) and 95% confidence interval (CI) to assess the clustering effect, using a multilevel (school and class) logistic regression. SARS-CoV-2 seroprevalence (IgM or IgG) was 21.8% and 23.8% (p = 0.575) in students and school staff, respectively. A total of 84 (8.6%) students and 35 (16.7%) school staff reported a previous molecular diagnosis. Among students, those who reported high-risk contacts only at school (OR = 1.13; 95% CI 0.72-1.78) had a seroprevalence similar to those without high-risk contacts; however, seroprevalence was significantly higher among those who only reported a high-risk contact outside the school (OR = 6.56; 95% CI 3.68-11.72), or in both places (OR = 7.83; 95% CI 5.14-11.93). Similar associations were found for school staff. The median OR was 1.00 (95% CI 1.00, 1.38) at the school-level and 1.78 (95% CI 1.40, 2.06) at the class-level. SARS-CoV-2 seroprevalence was similar between students and staff, without a clustering effect observed at the school level, and only a moderate clustering effect documented within classes. These results indicate that the mitigation measures in the school environment can prevent the spread of class outbreaks to the remaining school community.

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial.

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I-III (body mass index (BMI) 30.0-34.9 kg m-2, 35.0-39.9 kg m-2 and ≥40 kg m-2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511 .

COVID-19 vaccination and leprosy-A UK hospital-based retrospective cohort study.

BACKGROUND: Individuals with leprosy are at risk of leprosy reactions, T-cell mediated immunological complications, which lead to nerve function impairment. Leprosy reactions require systemic immunosuppression which is a risk factor for severe COVID-19. Vaccination for SARS-CoV-2 infection is recommended in the UK and became widely available in 2021 with individuals at increased risk of severe disease, including the immunosuppressed, prioritised. Vaccines for SARS-CoV-2 may provoke a T cell response. The latter poses a theoretical risk of provoking an immunological response to latent Mycobacterium leprae infection leading to clinical disease or in those with clinical disease triggering a leprosy reaction. BCG vaccination is associated with the development of leprosy in a small proportion of healthy contacts of people with leprosy within twelve weeks of administration. BCG causes a Th1 immune response. METHODOLOGY/PRINCIPAL FINDINGS: We performed a retrospective cohort study to determine the SARS-CoV-2 vaccination status of individuals diagnosed with leprosy attending the Leprosy Clinic in 2021 and whether any had developed leprosy or experienced a new leprosy reaction within twelve weeks of receiving a dose of a SARS-CoV-2 vaccine. The electronic patient records were used to retrieve data. Fifty-two individuals with leprosy attended the clinic in 2021 of which five people were newly diagnosed with leprosy. Thirty-seven (71%) were male and the median age was 48.5 years old (Range 27-85 years). Eight (15.4%) individuals were taking multi-drug therapy (MDT) and eight (15.4%) had completed MDT within three years of the study. Twenty-two (41.5%) individuals were prescribed a systemic immunosuppressant drug during 2021. Ten (18.9%) individuals have one or more risk factors for severe COVID-19. The SARS-CoV-2 vaccination status of fifty (96%) were recorded of which forty-nine were vaccinated (98%). One individual had declined vaccination. One individual was diagnosed with borderline tuberculoid (BT) leprosy having developed red skin lesions with reduced sensation (which increased in size and number) and thickened peripheral nerves one week after a second dose of BNT162b2 vaccine. Another individual who had completed MDT more than three years earlier developed red plaques and tender thickened nerves consistent with a leprosy Type 1 reaction eight weeks after a single dose of BNT162b2 vaccine (having received two doses of CoronaVac vaccine three months earlier). CONCLUSIONS/SIGNIFICANCE: The development of BT leprosy and a Type 1 reaction in another individual shortly after a dose of BNT162b2 vaccine may be associated with vaccine mediated T cell responses. The benefits of vaccination to reduce the risk of severe COVID-19 outweigh these unwanted events but data from leprosy endemic countries may provide further information about potential adverse effects of augmented T cell responses in individuals with leprosy or latent M. leprae infection.

Evaluation of acute toxicity and in vitro antitumor activity of a novel doxorubicin-loaded folate-coated pH-sensitive liposome.

Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative to administration of free drug. Therefore, new strategies are sought to improve DOX delivery and antitumor activity, while avoiding side effects. Recently, folate-coated pH-sensitive liposomes (SpHL-Fol) have been studied as a tool to enhance cellular uptake and antitumor activity of paclitaxel and DOX in breast cancer cells expressing folate receptor (FR+). However, the elucidation of folate functionalization relevance in DOX-loaded SpHL (SpHL-DOX-Fol) in different cell types (MDA-MB-231, MCF-7, and A549), as well as, the complete safety evaluation, is necessary. To achieve these objectives, SpHL-DOX-Fol was prepared and characterized as previously described. Antitumor activity and acute toxicity were evaluated in vivo through direct comparison of free DOX verses SpHL-DOX, a well-known formulation to reduce DOX cardiotoxicity. The obtained data are crucial to support future translational research. Liposomes showed long-term stability, suitable for biological use. Cellular uptake, cytotoxicity, and percentage of migration inhibition were significantly higher for MDA-MB-231 (FR+) treated with SpHL-DOX-Fol. In addition, SpHL-DOX-Fol demonstrated a decrease in the systemic toxic effects of DOX, mainly in renal and cardiac parameters evaluation, even using a higher dose (20 mg/kg). Collectively these data build the foundation of support demonstrating that SpHL-DOX-Fol could be considered a promising drug delivery strategy for the treatment of FR+ breast tumors.

Maternal consumption of caffeine and second-hand tobacco smoke as risk factors for the development of oral clefts.

OBJECTIVE: The aim of this case-control study was to investigate environmental factors, such as caffeine, folic acid, nutritional iron supplementation, multivitamin complexes, alcohol, and tobacco (second-hand smoking), which have been described as risk factors for the development of oral clefts. METHODS: This case-control study employed convenience sampling and included 409 mothers: 132 with children with oral clefts (cases) and 277 with children without oral clefts (controls). The age range of the children in both groups was 0 to 2 years. A questionnaire was administered to each mother to inquire about their habits and food consumption during the first trimester of pregnancy. RESULTS: Folic acid supplementation was observed in 116 (87.8%) of the case group (p < 0.001) and 271 (97.8%) of the control group. Regarding the use of ferrous sulfate, 114 (86.3%) of the case group and 271 (97.8%) of the control group reported using it. In the case group, 84 (63.6%) mothers reported being exposed to second-hand smoke, and 5 (3.7%) reported alcohol consumption (p = 0.797). In terms of caffeine consumption, 127 mothers (95.4%) in the case group consumed it (p = 0.13), while 247 (88.8%) reported consumption in the control group. CONCLUSIONS: The results suggest a direct relationship between secondhand smoke, alcohol consumption, and the lack of maternal supplementation with oral clefts.

Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography.

STUDY OBJECTIVES: We performed this study to describe the characteristics of sleep in children with congenital Zika syndrome through polysomnographic assessment. METHODS: Polysomnography with neurological setup and capnography was performed. Respiratory events were scored according to American Academy of Sleep Medicine criteria. Children were classified based on neuroclinical examination as having corticospinal plus neuromuscular abnormalities or exclusively corticospinal abnormalities. Neuroradiological classification was based on imaging exams, with children classed as having supratentorial plus infratentorial abnormalities or exclusively supratentorial abnormalities. RESULTS: Of 65 children diagnosed with congenital Zika syndrome, sleep apnea was present in 23 children (35.4%), desaturation in 26 (40%), and snoring in 13 (20%). The most prevalent apnea type was central in 15 children (65.2%), followed by obstructive apnea in 5 (21.7%) and mixed type in 3 (13%). The average of the lowest saturation recorded was slightly below normal (89.1 ± 4.9%) and the mean partial pressure of end-tidal carbon dioxide value was normal. Periodic leg movements were present in 48 of 65 children. Lower ferritin levels were observed in 84.6% of children. Palatine and pharyngeal tonsils (adenoids) were small in most children and not associated with the presence of obstructive apnea. Ventriculomegaly and subcortical and nucleus calcification were the most frequent neuroimaging findings. Supratentorial and infratentorial anomalies were present in 26.7% (16 of 60) and exclusively supratentorial changes in 73.3% (44 of 60). In the neuroclinical classification, isolated corticospinal changes were more frequent and the mean peak in capnography was lower in this group. There was no difference regarding the presence of apnea for children in the neuroclinical and neuroradiological classification groups. CONCLUSIONS: Sleep disorders were frequent in children with congenital Zika syndrome, with central sleep apnea being the main finding. CITATION: Brandão Marquis V, de Oliveira Melo A, Pradella-Hallinan M, et al. Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography. J Clin Sleep Med. 2023;19(10):1759-1767.