Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Antifungal efficacy in vitro e in vivo of miltefosine encapsulated in alginate nanoparticles on treatment of aspergilosis and systemic candidiasis.

As infecções fúngicas invasivas são consideradas grande problema de saúde pois acometem principalmente indivíduos imunocomprometidos e possuem espectro de tratamento muito limitado. Desse modo, a estratégia de reposicionamento se torna relevante e propõe-se a miltefosina (MFS) como potencial alternativa antifúngica pois apresenta amplo espectro de ação fungicida, porém a alta toxicidade pode dificultar o uso na micologia clínica. A utilização de sistemas nanoestruturados para liberação controlada e sustentada é uma maneira de reduzir a toxicidade e manter a atividade antifúngica e diante disso, a miltefosina encapsulada em nanopartículas de alginato (MFS-NA) se torna uma estratégia promissora na terapia de infecções fúngicas invasivas. Portanto, este trabalho teve como objetivo avaliar a atividade da MFS livre e MFS-NA sobre Aspergillus fumigatus (n=10), Aspergillus flavus (n=9) e Candida auris (n=2) em modelos experimentais in vitro e in vivo usando modelo larvário de Galleria mellonella. Os isolados de A. fumigatus testados foram considerados sensíveis para os antifúngicos padrão (anfotericina B AMB e voriconazol - VRC), enquanto as cepas de A. flavus exibiram um perfil mais tolerante. Utilizamos dois isolados de C. auris: CBS 10913 foi sensível a todos os antifúngicos convencionais e CBS 12766 apresentou resistência ao fluconazol. A MFS livre inibiu o crescimento fúngico em concentrações de 0,5 a 16 &#956g/mL; foi fungicida para a maioria das cepas de A. fumigatus e C. auris (1 a 32 &#956g/mL), e fungistático para A. flavus. A MFS-NA inibiu o crescimento de A. fumigatus, A. flavus e C. auris CBS 10913 em 18,7-600 &#956g/mL, enquanto C. auris CBS 12766 foi a mais tolerante (Concentração Inibitória Mínima CIM > 600 &#956g/mL). Foi identificado efeito sinérgico da MFS com VRC para o isolado 1220 de A. fumigatus, com redução da CIM em 8 vezes para ambos fármacos em combinação. Em modelo de G. mellonella, MFS (10 e 20 mg/kg) e da MFS-NA (100 mg/kg) reduziram a taxa de mortalidade e melhoraram o índice de saúde das larvas infectadas com A. fumigatus, além de reduzir a disseminação fúngica no tecido larval com o aumento da quantidade de granulomas de contenção da infecção. A combinação da MFS + VRC reduziu a carga fúngica e se mostrou melhor do que o tratamento apenas com VRC. Para infecção com A. flavus observou-se que quando combinado MFS-NA + VRC houve a melhora na taxa de sobrevivência além da diminuição da carga fúngica comparado com VRC, apontando que os tratamentos em combinação foram melhores que quando utilizados sozinhos. O perfil de sobrevivência em modelo de G. mellonella da cepa considerada muito virulenta de C. auris (CBS 12766) permaneceu o mesmo com os tratamentos, contudo, observou-se a diminuição da disseminação tecidual principalmente nos grupos tratados com MFS (40 mg/kg) e MFS-NA. Em contraste, MFS livre e MFS-NA foram efetivos contra a infecção por C. auris CBS 10913 levando ao aumento da sobrevivência larvária e redução da carga fúngica. A MFS livre e MFS-NA apresentam potencial relevante para a terapia antifúngica das aspergiloses e candidíases invasivas, e em combinação com VRC pode ser uma estratégia de melhoria do desempenho farmacológico nas terapias contra infecções fúngicas invasivas graves.Invasive fungal infections are considered a major health problem because they affect mainly immunocompromised patients and have a very limited spectrum of treatment. Thus, the repositioning strategy becomes relevant and miltefosine (MFS) is purposed as a potential antifungal alternative because presents broad spectrum of action fungicide, but the high toxicity may difficult the use in clinical mycology. The use of nanostructured systems for controlled and sustained release is a way to reduce toxicity and maintain antifungal activity and miltefosine encapsulated in alginate nanoparticles (MFS-AN) is a promising strategy in the therapy of invasive fungal infections. Therefore, this work aimed to evaluate the activity of free MFS and MFS-AN on Aspergillus fumigatus (n=10), Aspergillus flavus (n=9) and Candida auris (n=2) in experimental models in vitro and in vivo using larval model of Galleria mellonella. The isolates of A. fumigatus tested were considered sensitive to standard antifungals (amphotericin B - AMB and voriconazole - VRC) while the strains of A. flavus showed a more tolerant profile. We used two isolates of C. auris: CBS 10913 was sensitive to all conventional antifungals and CBS 12766 was resistant to fluconazole. Free MFS inhibited the fungal growth in concentrations from 0.5 to 16 &#956g/mL; it was fungicidal for most strains of A. fumigatus and C. auris (1 to 32 &#956g/mL), and fungistatic for A. flavus. MFS-NA inhibited the growth of A. fumigatus, A. flavus and C. auris CBS 10913 at 18.7-600 &#956g/mL, while C. auris CBS 12766 was the most tolerant (Minimum Inhibitory Concentration MIC > 600 &#956g/mL). The synergistic effect of MFS with VRC was identified for the isolate 1220 of A. fumigatus, with a reduction of MIC by 8 times for both drugs in combination. In the G. mellonella model, MFS (20 and 40 mg/kg) and MFS-NA (100 mg/kg) reduced the mortality rate and increased the health index of larvae infected with A. fumigatus, also reducing the fungal dissemination through the larval tissue with increase of the number of granulomas of the infection control. The combination of MFS + VRC reduced the fungal burden and showed to be better than treatment with VRC alone. For infection with A. flavus it was observed that when combined MFS-NA + VRC there was an increase of larvae survival, besides the reduction of fungal burden in comparison with VRC, indicating that the treatments in combination were better than when used alone. The survival profile in G. mellonella model of the strain considered to be more virulent (CBS 12766) remained the same with the treatments, nevertheless decreased tissue dissemination was observed mainly in the groups treated with MFS (40 mg/kg) and MFS-AN. In contrast, free MFS and MFS-AN were effective against infection with C. auris CBS 10913 leading to increase of larval survival and reduction of fungal burden. Free MFS and MFS-AN presents relevant potential for antifungal therapy of aspergillosis and invasive candidiasis, and in combination with VRC may be a strategy for improving pharmacological performance in therapy against several invasive fungal infections

Besifloxacin Nanocrystal: Towards an Innovative Ophthalmic Preparation

Bacterial conjunctivitis significantly impacts public health, including more than one-third of eye diseases reported worldwide. It is an infection caused by various aerobic and anaerobic bacteria and is highly contagious. Therefore, it has a high incidence of bacterial resistance to the antibiotics commonly used for treatment. Among the most recent antibiotics, besifloxacin is a fourth-generation fluoroquinolone antibiotic indicated exclusively for topical ophthalmic use. Due to its importance in treating bacterial conjunctivitis and its low solubility in water, limiting its efficacy, a nanotechnology-based drug delivery preparation was developed to overcome this hurdle. Besifloxacin nanocrystals were prepared by small-scale wet milling and response surface methodology, using Povacoat&reg; as a stabilizer. The particle&rsquo;s average hydrodynamic diameter (Z-ave) was approximately 550 nm (17 times smaller than raw material), with a polydispersity index (PdI) of less than 0.2. The saturation solubility increased about two times compared to the raw material, making it possible to increase the dissolution rate of this drug substance, potentially improving its bioavailability and safety. The optimized preparation was stable under an accelerated stability study (90 days). The Z-ave, PZ, PdI, and content did not alter significantly during this period. Furthermore, the 0.6% m/m besifloxacin nanocrystals at the maximum dose and the Povacoat&reg; stabilizer did not show toxicity in Galleria mellonella larvae. The innovative ophthalmic preparation minimum inhibitory concentration (MIC) was 0.0960 &micro;g/mL and 1.60 &micro;g/mL against Staphylococcus aureus and Pseudomonas aeruginosa, respectively, confirming in vitro efficacy. Therefore, besifloxacin nanocrystals revealed the potential for reduced dosing of the drug substance, with a minor occurrence of adverse effects and greater patient adherence to treatment

Núcleos de Ensino da Unesp: artigos 2008

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq