Effects of Vancomycin Subtherapeutic Concentration on Staphylococcus aureus Isolated from Hemodialysis Patients with Low Serum Trough Concentrations.

Blood bactericidal activity and antimicrobial therapy are crucial against catheter-related infection in patients undergoing hemodialysis (HD). It is well-known that catheters colonized by biofilm-producing bacteria are a risk factor for bacteremia in HD-patients. Methicillin-resistant S. aureus bacteremia in HD-patients justify the use of vancomycin as empiric therapy. The recommended vancomycin target for therapeutic efficacy is a minimum serum concentration of 10 µg mL-1 to avoid resistance. However, subtherapeutic concentrations of vancomycin have frequently occurred in HD-patients. Thus, we aim to investigate the effect of subtherapeutic vancomycin concentration on S. aureus growth, susceptibility to antimicrobials, resistance to whole blood activity, and biofilm formation. Seventeen S. aureus strains isolated from bacteremia in HD-patients and two reference strains were exposed to a vancomycin-gradient (0-10 µg mL-1) for five consecutive days to mimic the dosing interval of vancomycin in HD-patients. After that, we observed the following: no effect on growth curve; decreased susceptibility to vancomycin and daptomycin; increased S. aureus survival to whole blood bactericidal action; and a strain-dependent biofilm production after drug exposure. In conclusion, our findings suggest that the subtherapeutic concentration of vancomycin decrease S. aureus susceptibility to vancomycin and daptomycin and increases its survival to whole blood bactericidal action.

Hydroethanolic Extract of Grape Peel from Vitis labrusca Winemaking Waste: Antinociceptive and Anti-Inflammatory Activities.

Research background: Extracts from grape pomace, including the wine, show many biological effects such as antioxidant and anti-inflammatory activities. Unfortunately, winemakers discard the bagasse, so the waste is not exploited, although it contains bioactive compounds with antioxidant and anti-inflammatory properties. The work aims to analyze the hydroethanolic extract of peels from Vitis labrusca agro-industrial waste and to evaluate its antinociceptive and anti-inflammatory properties. This study is relevant for reusing a residue and adding value to the grape economic chain. Experimental approach: A representative sample of pomace was obtained and the peels were used to produce the extract. The phenolic compounds were determined by mass spectrometry in multiple reaction monitoring mode and Folin-Ciocalteu colorimetric method, using gallic acid as standard. The biological analyses were carried out using mice orally treated with crude extract at doses of 30, 100 and 300 mg/kg. We evaluated mechanical hyperalgesia by the von Frey method, thermal heat hyperalgesia using a hot plate at 55 °C, paw edema using a pachymeter, and neutrophil recruitment by measurement of myeloperoxidase activity. The nephrotoxicity and hepatotoxicity were evaluated by biochemical analyses using blood samples that were collected after the Vitis labrusca administration. Results and conclusions: In all wet winemaking residues peel mass fraction was 75%, and in dry residues 59%. We identified nine anthocyanins (3-O-glucosides: peonidin, delphinidin, petunidin and malvidin; 3-p-coumaroyl-glucosides: cyanidin, peonidin, petunidin and malvidin, and malvidin-3,5-diglucoside), five flavonoids (apigenin-7-glucoside, luteolin-7-glucoside, quercetin-3-galactoside, isorhamnetin-3-glucoside and myricetin-3-rutinoside), and mass fraction of phenolic compounds, expressed as gallic acid equivalents, was 26.62 mg/g. In vivo assays showed that Vitis labrusca extract at mass fractions 100 and 300 mg/kg reduced carrageenan-induced mechanical and thermal hyperalgesia, 50% of the paw edema, and neutrophil recruitment. In addition, there were no indications of nephrotoxicity and hepatotoxicity. Our extract obtained from winemaking residue has analgesic and anti-inflammatory properties, related at least in part to the presence of phenolic compounds, and it is not toxic to renal and hepatic tissues. Novelty and scientific contribution: This bio-product can be used as an alternative to synthetic anti-inflammatory agents with the same pharmacological potential and fewer side effects. We demonstrated that Vitis labrusca winemaking waste can be used for the production of antinociceptive and anti-inflammatory products (nutraceutical, pharmaceutical and cosmetics) without toxicity, contributing to the environmental economy.

Fractional model of COVID-19 applied to Galicia, Spain and Portugal.

A fractional compartmental mathematical model for the spread of the COVID-19 disease is proposed. Special focus has been done on the transmissibility of super-spreaders individuals. Numerical simulations are shown for data of Galicia, Spain, and Portugal. For each region, the order of the Caputo derivative takes a different value, that is not close to one, showing the relevance of considering fractional models.

Depression, disability and sleep disturbance are the main explanatory factors of fatigue in rheumatoid arthritis: a path analysis model.

OBJECTIVES: Fatigue is one of the most prevalent and disabling symptoms among patients with rheumatoid arthritis (RA), however, it is frequently neglected by health professionals. This study aimed to develop a multidimensional explanatory model of fatigue in patients with RA as a basis for better understanding and intervention. METHODS: This was an ancillary analysis of an observational, cross-sectional, single centre study. Patients completed a questionnaire including demographic data and measures of pain, sleep, disability, anxiety, depression, and personality. Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Disease activity and haemoglobin levels were assessed. Path analysis was performed to test and improve a hypothesised model for fatigue. RESULTS: This analysis included 142 patients, with a mean (SD) age of 61.1 (11.7) years. The final path analysis model presented acceptable fit and explained 60.0% of the variance of fatigue. The predominant direct explanatory factors identified were disability (46.5%) and depression (41.2%), the latter having an additional indirect influence of 19% through disability. Age (-16.2%) and sleep disturbance (15.7%) were also directly linked to fatigue. Personality trait extroversion (-22.4%), pain (20.0%), and disease activity (14.9%) are only indirectly related to fatigue. CONCLUSIONS: Depression, disability and sleep disturbance appear to be the main factors explaining fatigue in patients with RA. Disease activity, pain, and personality seem to play only a secondary role, extroversion being the only personality trait associated with fatigue. These findings foster a shift in the paradigm of care towards a more holistic management of fatigue, integrating adjunctive therapies beyond measures targeted solely at disease remission.

Hyaluronic acid hydrogels incorporating platelet lysate enhance human pulp cell proliferation and differentiation.

The restoration of dentine-pulp complex remains a challenge for dentists; nonetheless, it has been poorly addressed. An ideal system should modulate the host response, as well as enable the recruitment, proliferation and differentiation of relevant progenitor cells. Herein was proposed a photocrosslinkable hydrogel system based on hyaluronic acid (HA) and platelet lysate (PL). PL is a cocktail of growth factors (GFs) and cytokines involved in wound healing orchestration, obtained by the cryogenic processing of platelet concentrates, and was expected to provide the HA hydrogels specific biochemical cues to enhance pulp cells' recruitment, proliferation and differentiation. Stable HA hydrogels incorporating PL (HAPL) were prepared after photocrosslinking of methacrylated HA (Met-HA) previously dissolved in PL, triggered by the Ultra Violet activated photoinitiator Irgacure 2959. Both the HAPL and plain HA hydrogels were shown to be able to recruit cells from a cell monolayer of human dental pulp stem cells (hDPSCs) isolated from permanent teeth. The hDPCs were also seeded directly over the hydrogels (5 × 104 cells/hydrogel) and cultured in osteogenic conditions. Cell metabolism and DNA quantification were higher, in all time-points, for PL supplemented hydrogels (p < 0,05). Alkaline phosphatase (ALPL) activity and calcium quantification peaks were observed for the HAPL group at 21 days (p < 0,05). The gene expression for ALPL and COLIA1 was up-regulated at 21 days to HAPL, compared with HA group (p < 0,05). Within the same time point, the gene expression for RUNX2 did not differ between the groups. Overall, data demonstrated that the HA hydrogels incorporating PL increased the cellular metabolism and stimulate the mineralized matrix deposition by hDPSCs, providing clear evidence of the potential of the proposed system for the repair of damaged pulp/dentin tissue and endodontics regeneration.

Laterality of Pneumonia in Acute Stroke.

BACKGROUND/AIMS: Previous studies demonstrated an alteration of diaphragmatic excursion on the paretic side after stroke; however, it is unclear if this change has clinical repercussions. We aimed to determine if there was an association between the paretic side and the laterality of pneumonia after stroke. METHODS: A retrospective analysis of a consecutive cohort of patients admitted to a stroke unit from 2008 to May 2016 was performed. Patients with the diagnosis of acute stroke and pneumonia were included. The laterality of pneumonia was determined through the blinded observation of chest X-rays. Fisher's exact test was applied to study the association between the side of paresis and pneumonia. RESULTS: One hundred and five patients were included. Sixty one percent (n = 64) had an ischemic stroke, 39% (n = 41) had brain hemorrhage, and 49.5% (n = 52) had right side paresis. We did not find in general an association between the side of paresis and the side of pneumonia (p = 1.00); however, we found a statistically significant association in patients with severe lower limb paresis (Medical Research Council, MRC ≤2; p = 0.035). CONCLUSION: We found an association between severe paresis of the lower limb (MRC ≤2) and ipsilateral pneumonia. We hypothesize that the proximity between the diaphragmatic and inferior limb corticospinal pathways could be the reason for this association.

Cerebral Amyloid Angiopathy Associated with Inflammation: Report of 3 Cases and Systematic Review.

INTRODUCTION: Cerebral amyloid angiopathy associated with inflammatory process (CAA-I) is a rare potentially treatable encephalopathy, characterized by an inflammatory response to vascular deposits of ß-amyloid. We aimed to describe 3 clinical cases and perform a systematic review of all neuropathologically proved CAA-I case reports to describe its clinical and pathologic features and outcome under different treatments. METHODS: We searched PubMed and Cochrane Library and screened references of included studies and review articles for additional citations. Outcome was classified at the last available follow-up by the modified Rankin Scale (mRS). RESULTS: A total of 67 publications, reporting on 155 patients, were included. Mean age was 66.9 years, and 53.5% were men. The most common clinical presentation was cognitive dysfunction (48.0%) followed by headaches (38.7%), seizures (36.7%), and pyramidal signs (20.0%). Perivascular and vasculitic inflammation with granuloma was the most common pathologic pattern (27.5%). Eighty-six percent were treated with corticosteroids and 33.9% with cyclophosphamide. Forty-two percent regained independence (mRS score 0-2), whereas 20.5% were left with a severe handicap (mRS score 3-5) and 37.5% died. There were no statistically significant differences in outcome between patients treated with therapy with corticosteroids alone comparing with those treated with combination corticosteroids with cytostatic agents. CONCLUSIONS: The most common clinical manifestation of CAA-I was cognitive dysfunction. The functional outcome was unfavorable in the majority of the patients, with death or severe disability in almost two third of the cases, despite treatment. No differences in outcome could be detected between patients treated with corticosteroids versus patients treated with cytostatics, combined with corticosteroids.

Enumeration of salmonellae in table eggs, pasteurized egg products, and egg-containing dishes by using quantitative real-time PCR.

Salmonellae are a major cause of food-borne outbreaks in Europe, with eggs and egg products being identified as major sources. Due to the low levels of salmonellae in eggs and egg products, direct quantification is difficult. In the present study, enrichment quantitative real-time PCR (qPCR) was employed for enumeration of salmonellae in different matrices: table eggs, pasteurized egg products, and egg-containing dishes. Salmonella enterica serovar Enteritidis and S. enterica serovar Tennessee were used to artificially contaminate these matrices. The results showed a linear regression between the numbers of salmonellae and the quantification cycle (Cq) values for all matrices used, with the exception of pasteurized egg white. Standard curves were constructed by using both stationary-phase cells and heat-stressed cells, with similar results. Finally, this method was used to evaluate the fate of salmonellae in two egg-containing dishes, long egg and tiramisu, at abused refrigeration temperatures, and results indicated the growth of bacteria over a 1-week period. In conclusion, enrichment qPCR was shown to be reliable for enumeration of salmonellae in different egg products.

Cost-effectiveness analysis of optimal control measures for tuberculosis.

We propose and analyze an optimal control problem where the control system is a mathematical model for tuberculosis that considers reinfection. The control functions represent the fraction of early latent and persistent latent individuals that are treated. Our aim was to study how these control measures should be implemented, for a certain time period, in order to reduce the number of active infected individuals, while minimizing the interventions implementation costs. The optimal intervention is compared along different epidemiological scenarios, by varying the transmission coefficient. The impact of variation of the risk of reinfection, as a result of acquired immunity to a previous infection for treated individuals on the optimal controls and associated solutions, is analyzed. A cost-effectiveness analysis is done, to compare the application of each one of the control measures, separately or in combination.

Towards a neurocognitive profile in familial cerebral cavernous malformations.

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

Comparison of Blended Learning With Traditional Dermatology Learning for Medical Students: Prospective Evaluation Study.

BACKGROUND: Novel internet-based applications and associated technologies have influenced all aspects of society, ranging from commerce and business to entertainment and health care, and education is no exception. In this context, this study was designed to evaluate the impact of a dermatology e-learning program on the academic performance of medical students in dermatology. OBJECTIVE: The aim of this study is to develop a dermatology blended-learning course for undergraduate medical students, evaluate the knowledge gained by students exposed to this course, and compare the results to those of traditional teaching methods. METHODS: In this prospective study, we evaluated the performance of fourth-semester medical students at the Federal University of Bahia, Brazil. Students who had been in their second year of the medical course in 2019 were considered the control group, while students in their second year in 2020 were considered the blended or hybrid group. The first group attended traditional classes, using printed material (books and handouts), while the second group used our web-based course and e-book as a supplement in a hybrid web-plus-traditional fashion. Neither participants nor evaluators were blinded. The students in both groups were subjected to the same pre- and postcourse face-to-face, multiple-choice, paper-based evaluations, and we compared their performances. The content of the classes was the same for both groups. All didactic activities were developed by a team of certified dermatologists and professors from the university. RESULTS: A total of 129 students were selected and divided into 2 groups: the control group (n=57) and the hybrid group (n=72). The precourse tests did not indicate any difference between the control group (mean score 2.74, SD 1.25) and the hybrid group (mean score 3.2, SD 1.22 SD; P>.05). The hybrid group had better final-term grades (mean 8.18, SD 1.26) than the traditional group (mean 7.11, SD 1.04). This difference was statistically significant (P<.05). CONCLUSIONS: This study explores pedagogical possibilities in the field of dermatology teaching for medical school students. The results suggest that the performance of undergraduate students who attended the course with additional e-learning material was superior when compared to the performance of those who participated in the traditional course alone.

The relevance of the socio-emotional deficits in cerebral small vessels disease (CSVD): An exploratory study with sporadic CSVD and CADASIL patients.

Background: Cerebral Small Vessels Disease (CSVD) is categorized in different forms, the most common being the sporadic form and a genetic variant - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Amongst the most frequent clinical manifestations are the neuropsychological changes of cognitive, behavioral, and emotional nature, whose features are still under debate. Objective: This exploratory study aimed to compare the neuropsychological profile of a sporadic CSVD sample and a CADASIL sample with an age, education, and gender matched control group, between the ages of 30-65 YO (total sample mean age=51.16; SD=4.31). Methods: 20 patients with sporadic CSVD, 20 patients with CADASIL and 20 matched controls completed a neuropsychological assessment battery. Global cognitive state, processing speed, working memory, attention, executive dysfunction, episodic memory, social cognition, impulsivity, apathy, alexithymia, depression, and anxiety were measured. White matter hyperintensities (WMH) volume were quantified and measured as lesion burden. Results: The cognitive differences found between the clinical groups combined (after confirming no differences between the two clinical groups) and matched controls were restricted to speed processing scores (d = 0.32 95 % CI [.12-.47]). The socio-emotional and behavioral profile revealed significantly higher levels of depression (d = 0.21, 95 % CI [.16-.33]). and anxiety (d = 0.25 95 % CI [.19-.32]) in CADASIL and sporadic CSVD groups, and the same for the alexithymia score (d = 0.533 95 % CI [.32-.65]) were the clinical groups revealed impoverished emotional processing compared to controls. WMH only significantly correlated with the cognitive changes and age. Conclusions: In our study, CADASIL and sporadic cSVD patients combined, present multiple emotional-behavioral symptoms - alexithymia, anxiety, depression, and in a lower extent apathy and impulsivity - suggesting for the presence of emotion dysregulation behaviors, present independently of age and of the presence of cognitive deficits. Despite of the small sample size that could underpower some findings, this exploratory research supported that these symptoms may have a significant impact in disease monitoring, progression, and prognosis, requiring further investigation regarding their neurophysiological substrates.

Integrative taxonomy in the genus Rhabdias Stiles et Hassall, 1905 from anuran in Brazil, description of two new species and phylogenetic analyses.

About 20 valid species of the genus Rhabdias are known in the Neotropical region. The present study aimed to describe two new species of Rhabdias parasitizing the lungs of Leptodactylus macrosternum and Leptodactylus podicipinus from Brazil. Distinctive characteristics between these species are numerous and based on body size, size of the buccal capsule, shape and size of the oesophagus, and position of the vulva. Molecular data based on ribosomal genes 28S and ITS region and mitochondrial COI of the two species are presented. Molecular analysis and comparison of the partial mitochondrial COI sequence of Rhabdias matogrossensis n. sp. and Rhabdias guaianensis n. sp. revealed a genetic divergence between these new species and the sequences of Rhabdias spp. previously deposited in GenBank. In the phylogenetic analysis, R. matogrossensis n. sp. was grouped with R. breviensis species complex, and R. guaianensis n. sp. was grouped as a sister group of R. cf. stenochepala. This study contributes to improving the diversity of known species of Rhabdias described in Brazilian anurans.

Cutaneous larva migrans: a bad souvenir from the vacation.

Cutaneous larva migrans (CLM) is a common endemic disease in tropical and subtropical countries. This condition is caused by skin-penetrating larvae of nematodes, mainly of the hookworm Ancylostoma braziliense and other nematodes of the family Ancylostomidae. We report three cases of CLM acquired during vacations in different regions of Brazil.

Model-free based control of a HIV/AIDS prevention model.

Controlling an epidemiological model is often performed using optimal control theory techniques for which the solution depends on the equations of the controlled system, objective functional and possible state and/or control constraints. In this paper, we propose a model-free control approach based on an algorithm that operates in 'real-time' and drives the state solution according to a direct feedback on the state solution that is aimed to be minimized, and without knowing explicitly the equations of the controlled system. We consider a concrete epidemic problem of minimizing the number of HIV infected individuals, through the preventive measure pre-exposure prophylaxis (PrEP) given to susceptible individuals. The solutions must satisfy control and mixed state-control constraints that represent the limitations on PrEP implementation. Our model-free based control algorithm allows to close the loop between the number of infected individuals with HIV and the supply of PrEP medication 'in real time', in such a manner that the number of infected individuals is asymptotically reduced and the number of individuals under PrEP medication remains below a fixed constant value. We prove the efficiency of our approach and compare the model-free control solutions with the ones obtained using a classical optimal control approach via Pontryagin maximum principle. The performed numerical simulations allow us to conclude that the model-free based control strategy highlights new and interesting performances compared with the classical optimal control approach.

Complex network model for COVID-19: Human behavior, pseudo-periodic solutions and multiple epidemic waves.

We propose a mathematical model for the transmission dynamics of SARS-CoV-2 in a homogeneously mixing non constant population, and generalize it to a model where the parameters are given by piecewise constant functions. This allows us to model the human behavior and the impact of public health policies on the dynamics of the curve of active infected individuals during a COVID-19 epidemic outbreak. After proving the existence and global asymptotic stability of the disease-free and endemic equilibrium points of the model with constant parameters, we consider a family of Cauchy problems, with piecewise constant parameters, and prove the existence of pseudo-oscillations between a neighborhood of the disease-free equilibrium and a neighborhood of the endemic equilibrium, in a biologically feasible region. In the context of the COVID-19 pandemic, this pseudo-periodic solutions are related to the emergence of epidemic waves. Then, to capture the impact of mobility in the dynamics of COVID-19 epidemics, we propose a complex network with six distinct regions based on COVID-19 real data from Portugal. We perform numerical simulations for the complex network model, where the objective is to determine a topology that minimizes the level of active infected individuals and the existence of topologies that are likely to worsen the level of infection. We claim that this methodology is a tool with enormous potential in the current pandemic context, and can be applied in the management of outbreaks (in regional terms) but also to manage the opening/closing of borders.

Posterior reversible encephalopathy syndrome following Miller-Fisher syndrome.

A 71-year-old woman presented to the emergency room with dysphonia, diplopia, dysphagia and generalised weakness since that day. Neurological examination revealed eye adduction limitation, ptosis, hypoactive reflexes and gait ataxia. Blood and cerebrospinal fluid analysis and brain CT were normal. Electromyography revealed a sensory axonal polyneuropathy. She was diagnosed with Miller-Fisher syndrome (MFS) and started on intravenous immunoglobulin. Two days after intravenous immunoglobulin treatment was completed, she developed a sustained hypertensive profile and presented a generalised tonic-clonic seizure. Brain MRI was suggestive of posterior reversible encephalopathy syndrome (PRES) and supportive treatment was implemented with progressive improvement. PRES may be a possible complication of MFS not only due to autonomic and inflammatory dysfunctions, but also as a consequence of its treatment. Patients with MFS should be maintained under close surveillance, especially in the first days and preferably in intermediate care units.

Analysis of a COVID-19 compartmental model: a mathematical and computational approach.

In this note, we consider a compartmental epidemic mathematical model given by a system of differential equations. We provide a complete toolkit for performing both a symbolic and numerical analysis of the spreading of COVID-19. By using the free and open-source programming language Python and the mathematical software SageMath, we contribute for the reproducibility of the mathematical analysis of the stability of the equilibrium points of epidemic models and their fitting to real data. The mathematical tools and codes can be adapted to a wide range of mathematical epidemic models.