3D printed bioabsorbable composite scaffolds of poly (lactic acid)-tricalcium phosphate-ceria with osteogenic property for bone regeneration.

The fabrication of customized implants by additive manufacturing has allowed continued development of the personalized medicine field. Herein, a 3D-printed bioabsorbable poly (lactic acid) (PLA)- ß-tricalcium phosphate (TCP) (10 wt %) composite has been modified with CeO2 nanoparticles (CeNPs) (1, 5 and 10 wt %) for bone repair. The filaments were prepared by melt extrusion and used to print porous scaffolds. The nanocomposite scaffolds possessed precise structure with fine print resolution, a homogenous distribution of TCP and CeNP components, and mechanical properties appropriate for bone tissue engineering applications. Cell proliferation assays using osteoblast cultures confirmed the cytocompatibility of the composites. In addition, the presence of CeNPs enhanced the proliferation and differentiation of mesenchymal stem cells; thereby, increasing alkaline phosphatase (ALP) activity, calcium deposition and bone-related gene expression. Results from this study have shown that the 3D printed PLA-TCP-10%CeO2 composite scaffold could be used as an alternative polymeric implant for bone tissue engineering applications: avoiding additional/revision surgeries and accelerating the regenerative process.

Effect of Silicon Dioxide and Magnesium Oxide on the Printability, Degradability, Mechanical Strength and Bioactivity of 3D Printed Poly (Lactic Acid)-Tricalcium Phosphate Composite Scaffolds.

BACKGROUND: Poly (lactic acid) (PLA) is a biodegradable polyester that has been exploited for a variety of biomedical applications, including tissue engineering. The incorporation of ß-tricalcium phosphate (TCP) into PLA has imparted bioactivity to the polymeric matrix. METHODS: We have modified a 90%PLA-10%TCP composite with SiO2 and MgO (1, 5 and 10 wt%), separately, to further enhance the material bioactivity. Filaments were prepared by extrusion, and scaffolds were fabricated using 3D printing technology associated with fused filament fabrication. RESULTS: The PLA-TCP-SiO2 composites presented similar structural, thermal, and rheological properties to control PLA and PLA-TCP. In contrast, the PLA-TCP-MgO composites displayed absence of crystallinity, lower polymeric molecular weight, accelerated degradation ratio, and decreased viscosity within the 3D printing shear rate range. SiO2 and MgO particles were homogeneously dispersed within the PLA and their incorporation increased the roughness and protein adsorption of the scaffold, compared to a PLA-TCP scaffold. This favorable surface modification promoted cell proliferation, suggesting that SiO2 and MgO may have potential for enhancing the bio-integration of scaffolds in tissue engineering applications. However, high loads of MgO accelerated the polymeric degradation, leading to an acid environment that imparted the composite biocompatibility. The presence of SiO2 stimulated mesenchymal stem cells differentiation towards osteoblast; enhancing extracellular matrix mineralization, alkaline phosphatase (ALP) activity, and bone-related genes expression. CONCLUSION: The PLA-10%TCP-10%SiO2 composite presented the most promising results, especially for bone tissue regeneration, due to its intense osteogenic behavior. PLA-10%TCP-10%SiO2 could be used as an alternative implant for bone tissue engineering application.

Late patient-fitted total orbital reconstruction for facial gunshot wound sequelae.

Late reconstructions of gunshot wounds (GSWs) in the orbital area are a true challenge to the oral and maxillofacial surgeon. Usually, the wall defects are large in size and commonly present loss of orbital volume, which can cause ocular dystopia. The only exceptions are when there is an explosion of the orbital walls-that is, blow-out fractures. We encountered a patient with a two-year sequelae after GSW in the face that caused the destructed orbit to have a 2.5 bigger size than the contralateral orbit, requiring meticulous planning of a patient-specific implant (PSI) to correctly reconstruct the orbit volume and bone projection. The PSI was developed using titanium and it had three pieces that could reconstruct all four walls of the orbit. After surgery, the patient regained orbital volume and malar projection, allowing him to benefit from facial symmetry. The PSI can be used to reconstruct all the orbital walls in cases of complex bone defects.

Temporomandibular joint patient specific implant as treatment for hemifacial microsomia.

Hemifacial microsomia (HFM) is a complex congenital malformation with an extremely variable phenotypic presentation. It usually involves structures of the first and second pharyngeal arches. Anomalies of the cardiac, pulmonary, renal, and gastrointestinal systems are present, but the main characteristic is the mandibular hypoplasia. This is commonly treated with orthodontic hardware and various surgical modalities. Most recently, a total joint replacement with a customized prosthesis is idealized to provide the best outcomes to these patients, so it has been used in some cases. The following case is of a 23-year-old female with congenital hypoplastic mandibular head and the absence of mandibular fossa. The proposed treatment was to reconstruct the mandible with a customized prosthesis and orthognathic surgery to correct the asymmetry and provide better phonation, speech, and facial contour. The patient is under six years follow-up with a complete adaptation of the prosthesis.

Long-Term Clearance and Biodistribution of Magnetic Nanoparticles Assessed by AC Biosusceptometry.

Once administered in an organism, the physiological parameters of magnetic nanoparticles (MNPs) must be addressed, as well as their possible interactions and retention and elimination profiles. Alternating current biosusceptometry (ACB) is a biomagnetic detection system used to detect and quantify MNPs. The aims of this study were to evaluate the biodistribution and clearance of MNPs profiles through long-time in vivo analysis and determine the elimination time carried out by the association between the ACB system and MnFe2O4 nanoparticles. The liver, lung, spleen, kidneys, and heart and a blood sample were collected for biodistribution analysis and, for elimination analysis, and over 60 days. During the period analyzed, the animal's feces were also collectedd. It was possible to notice a higher uptake by the liver and the spleen due to their characteristics of retention and uptake. In 60 days, we observed an absence of MNPs in the spleen and a significant decay in the liver. We also determined the MNPs' half-life through the liver and the spleen elimination. The data indicated a concentration decay profile over the 60 days, which suggests that, in addition to elimination via feces, there is an endogenous mechanism of metabolization or possible agglomeration of MNPs, resulting in loss of ACB signal intensity.

The Influence of Omeprazole on the Dissolution Processes of pH-Dependent Magnetic Tablets Assessed by Pharmacomagnetography.

Pharmacomagnetography involves the simultaneous assessment of solid dosage forms (SDFs) in the human gastrointestinal (GI) tract and the drug plasmatic concentration, using a biomagnetic technique and pharmacokinetics analysis. This multi-instrumental approach helps the evaluation, as GI variables can interfere with the drug delivery processes. This study aimed to employ pharmacomagnetography to evaluate the influence of omeprazole on the drug release and absorption of metronidazole administered orally in magnetic-coated tablets. Magnetic-coated tablets, coated with Eudragit® E-100 (E100) and containing 100 mg of metronidazole, were produced. For the in vivo experiments, 12 volunteers participated in the two phases of the study (placebo and omeprazole) on different days to assess the bioavailability of metronidazole. The results indicated a shift as the pH of the solution increased and a delay in the dissolution of metronidazole, showing that the pH increase interferes with the release processes of tablets coated with E100. Our study reinforced the advantages of pharmacomagnetography as a tool to perform a multi-instrumental correlation analysis of the disintegration process and the bioavailability of drugs.

Shorter telomeres in children with severe asthma, an indicative of accelerated aging.

Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.

Cystic Fibrosis: A Simple and Customized Strategy for Genetic Screening Able to Detect Over 90% of Identified Mutated Alleles in Brazilian Newborns.

INTRODUCTION: The incorporation of molecular genetic testing into cystic fibrosis (CF) screening programs increases the specificity of the diagnostic strategy and has the potential to decrease the rate of false- positive results. In this sense, our objective was to develop a genotyping assay that could detect 25 pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene with high sensitivity and that could be incorporated into the routine of newborn screening, complementing the current existing protocol used in our public health institution. METHODS: A mini-sequencing assay was standardized using single-base extension in a previously genotyped control sample. This strategy was validated in a Brazilian cohort of CF patients by Sanger sequencing. RESULTS: The inclusion of the 25 variants in the current newborn screening program increased the identification rates of two alleles from 33 to 52.43% in CF patients. This new approach was able to detect a total of 37 variants, which represents 93.01% of all mutated alleles described in the last CF Brazilian Register. CONCLUSIONS: Mini-sequencing for the simultaneous detection of 25 CFTR gene variants improves the screening of Brazilian newborns and decreases the number of inconclusive cases. This method uses minimal hands-on time and is suited for rapid screening, which reduces sample processing costs.

AC biosusceptometry and magnetic nanoparticles to assess doxorubicin-induced kidney injury in rats.

Aim: This paper aims to investigate a doxorubicin (DOX) chronic kidney disease rat model using magnetic nanoparticles (MNPs) associated with the alternate current biosusceptometry (ACB) to analyze its different perfusion profiles in both healthy and DOX-injured kidneys. Materials & methods: We used the ACB to detect the MNP kidney perfusion in vivo. Furthermore, we performed biochemical and histological analyses, which sustained results obtained from the ACB system. We also studied the MNP biodistribution. Results: We found that DOX kidney injury alters the MNPs' kidney perfusion. These changes became more intense as the disease progressed. Moreover, DOX has an important effect on MNP biodistribution as the disease evolved. Conclusion: This study provides new applications of MNPs in nephrology, instrumentation, pharmacology, physiology and nanomedicine.

Impact of maternal dTpa vaccination on the incidence of pertussis in young infants.

INTRODUCTION: Pertussis is an important public health problem worldwide, especially in infants. An increase in the incidence in many countries occurred after 2010, including Brazil. In 2013, dTpa vaccine was introduced in the Brazil national immunization schedule of pregnant women. The objective of this study was to evaluate the national trends in the incidence of pertussis in Brazil in children under 1 year old, and the impact of the introduction of dTpa vaccine during pregnancy. METHODS: The incidence of hospitalizations and non-hospitalized confirmed cases of pertussis in neonates (< 1 month age) and young infants (1 month-< 1 year age) were analyzed, comparing the incidence in pre maternal vaccination (2011-2013) with the post-vaccination (2015-2017). We used non-respiratory hospitalizations as comparison, during the same period. A database of the Brazilian Ministry of Health (DATASUS) was used to analyze cases from 2007 to 2017 and the subsets of 2011-2013 and 2015-2017, after Pertussis resurgence. The vaccination data was accessed through the link of the Information System of the National Immunization Program (pni.datasus.gov.br). RESULTS: Between 2007 and 2017, 17,818 children under one year of age were hospitalized due to pertussis in Brazil. In the pre maternal vaccination period 2011-2013, the mean annual incidence of non-hospitalized confirmed cases of pertussis in children under 1 month was 722.2 / 100,000 and in the period of 2015-2017 the average was 377.3 / 100,000, representing a decrease of 47.7% [IRR 0.52 (0.46-0.59)]. At those periods of time, the average incidence per year for children of one month-< 1 year aged was 64.9 / 100,000 (2011-2013) and 29.3 / 100,000 (2015-2017) [IRR 0.45 (CI 0.29-0.69)]. CONCLUSION: Vaccination of pregnant woman coincides with the reduction in the number of cases of pertussis in children under 1 month of age from 2015. Immunization of pregnant woman seems to have an important impact on the prevention of the disease in young infants who have not yet received their own pertussis vaccine.

Multichannel AC Biosusceptometry System to Map Biodistribution and Assess the Pharmacokinetic Profile of Magnetic Nanoparticles by Imaging.

In this paper, the application of a technique to evaluate in vivo biodistribution of magnetic nanoparticles (MNP) is addressed: the Multichannel AC Biosusceptometry System (MC-ACB). It allows real-time assessment of magnetic nanoparticles in both bloodstream clearance and liver accumulation, where a complex network of inter-related cells is responsible for MNP uptake. Based on the acquired MC-ACB images, we propose a mathematical model which helps to understand the distribution and accumulation pharmacokinetics of MNP. The MC-ACB showed a high time resolution to detect and monitor MNP, providing sequential images over the particle biodistribution. Utilizing the MC-ACB instrument, we assessed regions corresponding to the heart and liver, and we determined the MNP transfer rates between the bloodstream and the liver. The pharmacokinetic model resulted in having a strong correlation with the experimental data, suggesting that the MC-ACB is a valuable and accessible imaging device to assess in vivo and real-time pharmacokinetic features of MNP.

Impact of omalizumab in children from a middle-income country with severe therapy-resistant asthma: A real-life study.

BACKGROUND: Severe asthma in children is a global health problem. Severe therapy-resistant asthma (STRA) in children is a major clinical challenge due to persistent symptoms despite high doses of corticosteroids and results in high public health costs. Omalizumab (anti-IgE monoclonal antibody) has been described as an effective add-on therapy in these patients. The characteristics of children with STRA from low- and middle-income countries have scarcely been reported, and no real-life study has been published on the effects of omalizumab in this group of patients. The aim of our study is to report the first clinical real-life experiences with omalizumab in Brazilian children with STRA. METHODS: Children (6-18 years old) from a referral center who were diagnosed with STRA were included in this retrospective study based on our clinical databases. The included children had undergone at least 6 months of omalizumab treatment and fulfilled the following initial criteria: 1) >6 years old; 2) a positive skin-prick test for at least one aeroallergen; and 3) a serum total IgE level between 30 and 1500 IU/mL. Clinical and lung function variables were analyzed before and after treatment. RESULTS: Fourteen children (mean age: 11.9 years; percentage female: 72%) were included in this study. Omalizumab treatment significantly increased control of the disease according to a standardized questionnaire administered at every visit (P < 0.0001), ceased hospitalizations in 70% (P = 0.02) of patients, and allowed 8/9 (89%) patients to be weaned off oral steroids (P = 0.004). CONCLUSIONS: In this retrospective report, the use of omalizumab in Brazilian children with STRA significantly improved disease control, decreased hospitalizations, and allowed suspension of continuous oral corticosteroids.

Asthma and Obesity in Children Are Independently Associated with Airway Dysanapsis.

BACKGROUND: An increase in the prevalence of overweight and asthma has been observed. Both conditions affect negatively lung function in adults and children. The aim of this study was to analyze the effect of overweight and asthma on lung function in children. METHODS: We designed a case-control study of healthy and asthmatic subjects nested within an epidemiological asthma prevalence study in children between 8 and 16 years of age. The effect of asthma and overweight on lung function was assessed by impulse oscillometry and spirometry obtained at baseline and 10-15 min after salbutamol. RESULTS: 188 children were recruited, 114 (61%) were asthmatics and 72 (38%) were overweight or obese. Children with asthma and overweight had a higher FVC (+1.16 z scores, p < 0.001) and higher FEV1 (+0.79 z scores, p = 0.004) and lower FEV1/FVC (-0.54 z scores, p = 0.008) when compared to healthy controls. Compared to normal weight asthmatics, the overweight had higher FVC (+0.78 z scores, p = 0.005) and lower FEV1/FVC (-0.50 z scores, p = 0.007). In the multivariate analysis, overweight was associated with an increase of 0.71 and 0.44 z scores in FVC and FEV1, respectively, and a reduction in FEV1/FVC by 0.40 z scores (p < 0.01 for all). Overweight had no effect on maximal flows and airway resistance at baseline, and this was not modified by inhalation of a bronchodilator. Asthma was also associated with higher post-BD FVC (0.45 z scores, p = 0.012) and FEV1 (0.35 z scores, p = 0.034) but not with FEV1/FVC and FEF25-75%. Two-way analysis of variance did not detect any interaction between asthma and overweight on lung function variables before or after bronchodilator. CONCLUSION: Our results suggest that asthma and overweight are independently associated with airway dysanaptic growth in children which can be further scrutinized using impulse oscillometry. Overweight contributed more to the reduction in FEV1/FVC than asthma in children without increasing airway resistance. Spirometry specificity and sensitivity for obstructive diseases may be reduced in populations with high prevalence of overweight. Adding impedance oscillometry to spirometry improves our understanding of the ventilatory abnormalities in overweight children.

Free asthma medications reduces hospital admissions in Brazil (Free asthma drugs reduces hospitalizations in Brazil).

BACKGROUND: Since June 2011, the Brazilian health system started providing asthma medications (beclomethasone and salbutamol), totally free of charge to patients with asthma. The aim of this study was to evaluate the impact of the provision of free asthma medications on hospital admissions for asthma in Brazil, using a national hospitalization database (DATASUS), comparing the incidence of hospital admissions before and after the free supply of these drugs. METHODS: Admissions of patients with 1-49 years of age by the Brazilian public health system with the diagnosis of asthma were compared pre (2008-2010) and post (2012-2014) provision of free medicines (beclomethasone and salbutamol). The number of hospital admissions due to asthma and non-respiratory diseases, as well as the amount spent with asthma hospitalization, were obtained from DATASUS, the Brazilian government open-access public health database system. RESULTS: Admission rates for asthma significantly decreased from 90.09/100.000 (2008-2010) to 59.85/100.000 (2012-2014), when the period pre and post provision of free medicines were compared [OR 0.67 (CI 0.48-0.92)]. Non-respiratory admission rates remained stable, when both periods were also compared. CONCLUSION: Asthma hospitalization rates significantly decreased in the three-year period after the provision of free medicines to treat asthma. Our findings suggest that the provision of free medications for asthma may have a particular public health impact by its own in developing countries.

Effects of an educational intervention of physical activity for children and adolescents with cystic fibrosis: a randomized controlled trial.

BACKGROUND: Regular aerobic exercise in patients with cystic fibrosis (CF) improves aerobic conditioning and delays disease progression, resulting in better quality of life. The purpose of this study was to evaluate the effect of an aerobic exercise program based on verbal and written guidelines on maximum exercise capacity using a cardiopulmonary exercise test, quality of life, and the self-reported aerobic exercise practice of children and adolescents with CF. METHODS: This randomized controlled trial followed guidelines for physical exercise in a CF center. Subjects were assigned to 2 groups: intervention (group 1), with 17 subjects; and control (group 2), also with 17 subjects. Data were collected from October 2010 to October 2011, and the study population comprised 7-20-y-old children and adolescents with CF. The intervention consisted of handing out a manual with guidelines for aerobic physical exercises and reinforcing recommendations in telephone calls every 2 weeks. RESULTS: Thirty-four subjects were included in the study, 20 of whom were boys (58.5%). The groups were similar at baseline. In group 1, 6 subjects (35.2%) reported practicing physical exercises regularly. The mean age was 13.4 ± 2.8 y, the mean percent-of-predicted FEV1 was 95.5 ± 17.9%, and the mean peak oxygen uptake (V̇O2 ) relative to body mass was 34.9 ± 9.0 mL/kg/min. In group 2, 4 subjects (23.5%) reported practicing physical exercises regularly. The mean age was 12.7 ± 3.3 y, the mean percent-of-predicted FEV1 was 100.1 ± 21.2%, and the mean peak V̇O2 was 33.2 ± 8.2 mL/kg/min. In group 1, there was a significant increase in physical exercise practice as reported by subjects after 3 months of intervention compared with group 2 (P = .01). No statistically significant differences were found for the other variables. CONCLUSIONS: Verbal and written guidelines for aerobic exercise, together with supervision over the telephone, had a positive impact on the self-reported regular physical exercise practice of children and adolescents. However, no improvement was found in lung function and maximum exercise capacity or domains of the quality of life questionnaire.

Impact of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on childhood pneumonia hospitalizations in Brazil two years after introduction.

INTRODUCTION: Pneumococcal disease is a major public health problem worldwide. From March to September of 2010, 10-valent pneumococcal non-typeable Haemophilus influenzae protein conjugate vaccine (PHiD-CV) was introduced in the Brazilian childhood National Immunization Program (NIP) in all 27 Brazilian states. The aim of the present study is to report national time-trends in incidence of hospital admissions for childhood pneumonia in Brazil before and after two years of introduction of this new pneumococcal conjugate vaccine. METHODS: Analysis of hospitalization data of children aged 0-4 years in Brazilian public health system with an admission diagnosis of pneumonia from 2002 to 2012 was performed comparing pre (2002-2009) and post-vaccination periods (2011-2012). Hospital number of admission due to pneumonia and all non-respiratory diseases were obtained from DATASUS, the Brazilian government open-access public health database system. Incidence of pneumonia hospitalization was compared to incidence of all non-respiratory admissions. RESULTS: Admission rates for pneumonia decreased steadily from 2010 to 2012. In children aged less than four years, incidence of pneumonia hospitalizations decreased 12.65% when pre (2002-2009) and post-vaccination introduction periods (2011-2012) were compared and adjusted for seasonality and secular-trend (p<0.001). On the other hand, non-respiratory admission rates remained stable comparing both periods (p=0.39). CONCLUSION: Childhood pneumonia hospitalization rates were fluctuating prior to 2010 and decreased significantly in the two years after PHiD-CV introduction. Conversely, rate of non-respiratory admissions has shown no decrease. These data are an evidence of the effectiveness and public health impact of this new pneumococcal vaccine.

Investigação e manejo da febre em lactentes e pré-escolares / Investigation and management of fever in infants and pre-school children

Este trabalho visa apresentar uma revisão de um sintoma bastante freqüente nas consultas pediátricas, a febre. A investigação sempre deve ser realizada considerando o grupo etário. O tratamento pode ser sintomático, nos casos de infecções virais benignas, ou específico dependendo da suspeita ou confirmação de infecções invasivas.

This article is here to present a review about one of the most frequent symptoms in pediatrics, the fever. The investigation must always involve the age range. The treatment can be symptomatic, in the cases involving viral infections; Otherwise it can be specific, depending on the diagnostic hypothesis or confirmation of invasive infections

Azithromycin therapy in hospitalized infants with acute bronchiolitis is not associated with better clinical outcomes: a randomized, double-blinded, and placebo-controlled clinical trial.

OBJECTIVE: To test the hypothesis that azithromycin reduces the length of hospitalization and oxygen requirement in infants with acute viral bronchiolitis (AB). STUDY DESIGN: We performed a randomized, double-blinded, placebo-controlled trial in southern Brazil, from 2009 to 2011. Infants (<12 months of age) hospitalized with AB were recruited in 2 hospitals. Patients were randomized to receive either azithromycin or placebo, administered orally, for 7 days. At enrollment, clinical data were recorded and nasopharyngeal samples were collected for viral identification through immunofluorescence. Main outcomes were duration of oxygen requirement and length of hospitalization. RESULTS: One hundred eighty-four patients were included in the study (azithromycin 88 subjects, placebo 96 subjects). Baseline clinical characteristics and viral identification were not different between the groups studied. A virus was detected in 112 (63%) patients, and of those, 92% were positive for respiratory syncytial virus. The use of azithromycin did not reduce the median number of days of either hospitalization (P = .28) or oxygen requirement (P = .47). CONCLUSIONS: Azithromycin did not improve major clinical outcomes in a large sample of hospitalized infants with AB, even when restricting the findings to those with positive respiratory syncytial virus samples. Azithromycin therapy should not be given for AB because it provides no benefit and overuse increases overall antibiotic resistance.