Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Fractional order controllers increase the robustness of closed-loop deep brain stimulation systems.

We studied the effects of using fractional order proportional, integral, and derivative (PID) controllers in a closed-loop mathematical model of deep brain stimulation. The objective of the controller was to dampen oscillations from a neural network model of Parkinson's disease. We varied intrinsic parameters, such as the gain of the controller, and extrinsic variables, such as the excitability of the network. We found that in most cases, fractional order components increased the robustness of the model multi-fold to changes in the gains of the controller. Similarly, the controller could be set to a fixed set of gains and remain stable to a much larger range, than for the classical PID case, of changes in synaptic weights that otherwise would cause oscillatory activity. The increase in robustness is a consequence of the properties of fractional order derivatives that provide an intrinsic memory trace of past activity, which works as a negative feedback system. Fractional order PID controllers could provide a platform to develop stand-alone closed-loop deep brain stimulation systems.

Análisis del tiempo de vida útil en la elaboración de mermelada de higuerón (Cucúrbita Odorífera Vell) con zanahoria (Daucus Carota) / Time analysis of life in the development of marmalade higuerón (Cucurbita Odorifera Vell) with carrot (Daucus Carota)

The aim of this study was to determine the lifespan in making jam by higueron and carrot mixture, motivated by the lack of a number of species of tubers and vegetables, as evidenced by the low consumption of these foods and the lack of appropriate technology for processing the same. The two raw materials are high in vitamins and minerals, higueron suitable for their characteristics and chemical composition is considered a fruit-vegetable, it is possible it industrialization similar to those made with fruits, like the carrot is a food products excellent from the nutritional point of view, contributing to improve the quality of the jam. The treatments were kept under ambient conditions for 40 days when pH were recorded - soluble solids (° Brix) - Heartburn - Microbiological and organoleptic analysis in order to identify the best experimental treatment tests. According to the results obtained and microbiological analysis establishes a lifetime about 6 months.

El objetivo de este estudio fue conocer el tiempo de vida útil en la elaboración de mermelada mediante una mezcla higuerón y zanahoria, motivado por el desconocimiento de un sinnúmero de especies de tubérculos y hortalizas, evidenciado por el bajo consumo de estos alimentos y la carencia de tecnología adecuada para el procesamiento del mismo y aprovechamiento de sus nutrientes. Las dos materias primas de alto contenido de vitaminas y minerales; el higuerón se considera como fruta-hortaliza por sus características y composición química, siendo posible la industrialización en productos semejantes a los elaborados con las frutas. La zanahoria es un alimento excelente desde el punto de vista nutricional por lo que aporta al mejoramiento de la calidad de la mermelada. Los tratamientos se mantuvieron bajo condiciones ambientales durante 40 días en los que se registró pH - sólidos solubles (°Brix) - acidez - análisis microbiológicos y pruebas organolépticas con la finalidad de identificar el mejor tratamiento experimental. De acuerdo a los resultados obtenidos y al análisis microbiológico se establece un tiempo de vida útil alrededor de 6 meses.

Centripetal focusing of gyrotactic phytoplankton.

A suspension of gyrotactic microalgae Chlamydomonas augustae swimming in a cylindrical water vessel in solid-body rotation is studied. Our experiments show that swimming algae form an aggregate around the axis of rotation, whose intensity increases with the rotation speed. We explain this phenomenon by the centripetal orientation of the swimming direction towards the axis of rotation. This centripetal focusing is contrasted by diffusive fluxes due to stochastic reorientation of the cells. The competition of the two effects lead to a stationary distribution, which we analytically derive from a refined mathematical model of gyrotactic swimmers. The temporal evolution of the cell distribution, obtained via numerical simulations of the stochastic model, is in quantitative agreement with the experimental measurements in the range of parameters explored.

Sodium hyaluronate improves quality of life and nasal endoscopy features in preschool children with upper respiratory tract infections.

The aim of this prospective, randomised study was to evaluate the effects of nasal douches with sodium hyaluronate on clinical and endoscopic variables, on parental perception of their child’s health-related quality of life (HR-QoL), and on parental workdays lost in preschool recurrent upper respiratory tract infections (URTIs). Children aged 2-6 years with recurrent or persistent URTIs underwent at baseline the evaluation of upper respiratory tract symptoms in the previous two weeks, and nasal endoscopy. Parents of enrolled children were assessed for self-perception of their children’s HR-QoL using a standardised questionnaire. The same variables were reassessed after a 2-week treatment with either 9 mg sodium hyaluronate plus saline solution or saline alone by nasal douches. Forty of the 48 children enrolled completed the study (22 assigned to the combined treatment). Compared to baseline, the combined treatment resulted in a significant reduction of the prevalence of children with missed daycare days (45% vs 14%, p=0.04) and of parents with workdays lost (36% vs 5%, p=0.02), and in a significant improvement of HR-QoL score (3.7 vs 2.8, p=0.004). At endoscopy, the secretion and mucosal oedema score significantly improved after the combined treatment (6 vs 2, p < 0.001), and there was a trend towards a reduction of the adenoid hypertrophy score (p=0.06). No clinical, HR-QOL or endoscopy changes were found in the saline group. In preschool children with recurrent or persistent URTIs, sodium hyaluronate by nasal douche significantly improves endoscopic features. Additional benefits include the children’s HR-QoL and daycare attendance, and parental work.

Desempenho produtivo e econômica de surubins (pseudoplatystoma sp) alimentados com níveis de proteína e estocados em tanque-rede / Growth performance and economic of pseudoplatystoma sp fed with protein levels reared in net cages

O surubim (Pseudoplatystoma sp.) é uma das espécie de peixe mais apreciadas para o consumo. Por ser uma espécie carnívora, exige atenção especial no que tange às suas exigências nutricionais. Até o momento, poucos estudos foram realizados para estabelecê-las na fase de engorda, em especial em sistema de cultivo intensivo. O objetivo do presente estudo foi avaliar os desempenhos zootécnico e econômico de surubins (Pseudoplatystoma sp.) na fase final de crescimento, estocados em tanque-rede e alimentados com dietas com diferentes níveis de proteína. Os peixes, com peso de 356,6±40,3g, foram acondicionados em 12 tanques-rede de 18m3, nos quais permaneceram por cinco meses até adquirirem o peso comercial para abate. O tratamento experimental foi constituído por três dietas extrusadas comerciais, com os níveis de proteína bruta (36, 38, 40%PB) sendo substituídos gradativamente por carboidratos. Foram avaliados os parâmetros de crescimento, rendimento de filé, enzimas metabólicas e desempenho econômico. O ganho de peso, o ganho de peso diário, o consumo de dieta, a taxa de eficiência proteica, a sobrevivência e o rendimento de filé não apresentaram diferença significativa. A conversão alimentar foi melhor para os peixes alimentados com a dieta com 38 e 40%PB. Não foram observadas diferenças significativas para os parâmetros de índice hepatossomático e de enzimas hepáticas. Apesar dos maiores gastos com a ração contendo 38%PB em comparação à dieta com 36%PB, esta foi a que apresentou o melhor índice de custo por kg de peixe produzido. Os melhores índices de crescimento e o menor custo de arraçoamento foram obtidos pelos peixes alimentados com a dieta 38%PB, sendo esta, portanto recomendada para o arraçoamento na fase final de surubins em tanque-rede.

The Pseudoplatystoma sp. is one of the most appreciated fish species for consumption. Being a carnivorous species, the painted requires special attention regarding their nutritional requirements. To date, few studies have been conducted to establish them in their stage of fattening especially in intensive cultivation systems. The aim of the present study was to evaluate the growth and economic performance of Pseudoplatystoma sp fed with protein levels reared in net cages. The fish weighing from 356.6 ± 40.3g were packed in twelve net cages in 18 m3 in which they remained for five months until acquiring the commercial weight for slaughter. The experimental treatment was constituted by three commercial extruded diets with different crude protein levels (36, 38, 40% CP) gradually being replaced with carbohydrate. Growth parameters, metabolic enzymes, fillet yield and economic performance were evaluated. The gain in weight, daily weight gain, diet consumption, protein efficiency rate, survival and fillet yield did not show significant difference. The feed conversion was best for fish fed a diet with 38 and 40% CP. No significant differences were observed for the hepatossomatic index parameters and liver enzymes. There were larger expenditures on rations containing 38% PB compared to the diet with 36% CP, this presented the best index of cost per kg of fish produced. The best growth rates and lower cost of feeding were obtained by fish fed with a 38% CP diet, which is, therefore, recommended for feeding in the final phase of surubins monitored via net cages.

Nanoparticle assisted photothermal deformation of individual neuronal organelles and cells.

Stimulation of the localized surface plasmon of metallic nanoparticles has been shown to be an effective mechanism to induce photothermal damage in biological tissues. However, few studies have focused on single cell or subcellular ablation. Our results show that, upon incubation, gold nanostars are internalized by neurons of acute mouse cerebellar brain slices, clustering inside or close to the nucleus. By stimulating the nanostars' surface plasmon using a femtosecond laser, we show deformation of single nuclei and single cells. Given its precision and extremely localized effect, this is a promising technique for photothermal therapy in areas sensitive to collateral thermal damage such as the nervous system.

[Health consequences of obesity in children and adolescents]. / Conseguenze dell'obesità sulla salute del bambino e dell' adolescente.

Obesity in childhood is associated with the presence of complications that can undermine health immediately or in the long term. Several conditions, such as pulmonary or orthopedic complications are strictly associated with the severity of overweight, since they are directly associated to the mechanic stress of fat tissue on the airways or on the bones. Other conditions, such as metabolic or liver complications, although increasing with the extent of overweight, are associated with insulin resistance, which can be modulated by different other factors (ethnicity, genetics, fat distribution) and can occur in overweight children as well. No less important are psychological correlates, such as depression and stigma, which can seriously affect the health related quality of life. Pediatric services for the care of childhood obesity need to be able to screen overweight and obese children for the presence of physical and psychological complications, which can be still reversed by weight loss. This article provides pediatricians a comprehensive update on the main complications in obese children and adolescents and their treatment.

Obesity and pulmonary disease: unanswered questions.

Obesity is associated with risk of pulmonary disease, and adversely affects lung function. The parallel increase in obesity and asthma suggests the two conditions are linked; indeed, they can worsen each other. Obesity and inadequate asthma control are associated with poor quality of life, and place a high economic burden on public health. Although the obesity-lung interaction is a major issue for basic research and clinical studies, various questions remain unanswered. Do intrauterine and early life factors impact on the development of obesity and lung disease? If so, can this be prevented? Asthma is generally more severe in obese subjects, but is adiposity a driver of a new asthma phenotype that features greater morbidity and mortality, worse control and decreased response to medications? Obese individuals have small lung volumes, hence their airway calibre is reduced and airway resistance is increased. What puzzles physicians is whether peripheral airways undergo remodelling, which would increase bronchoconstriction. Obese asthmatics respond suboptimally to anti-inflammatory treatment, which raises the question: 'what drug for what patient?' Life expectancy is decreased in obesity and in chronic pulmonary disorders, but does obesity protect against or trigger chronic obstructive pulmonary disease? The time has come to find answers to these questions.

Near-unity quantum yields of biexciton emission from CdSe/CdS nanocrystals measured using single-particle spectroscopy.

Biexciton photoluminescence (PL) quantum yields (Q(2X)) of individual CdSe/CdS core-shell nanocrystal quantum dots with various shell thicknesses are derived from independent PL saturation and two-photon correlation measurements. We observe a near-unity Q(2X) for some nanocrystals with an ultrathick 19-monolayer shell. High Q(2X)'s are, however, not universal and vary widely among nominally identical nanocrystals indicating a significant dependence of Q(2X) upon subtle structural differences. Interestingly, our measurements indicate that high Q(2X)'s are not required to achieve complete suppression of PL intensity fluctuations in individual nanocrystals.

Nano-engineered electron-hole exchange interaction controls exciton dynamics in core-shell semiconductor nanocrystals.

A strong electron-hole exchange interaction (EI) in semiconductor nanocrystals (NCs) gives rise to a large (up to tens of meV) splitting between optically active ('bright') and optically passive ('dark') excitons. This dark-bright splitting has a significant effect on the optical properties of band-edge excitons and leads to a pronounced temperature and magnetic field dependence of radiative decay. Here we demonstrate a nanoengineering-based approach that provides control over EI while maintaining nearly constant emission energy. We show that the dark-bright splitting can be widely tuned by controlling the electron-hole spatial overlap in core-shell CdSe/CdS NCs with a variable shell width. In thick-shell samples, the EI energy reduces to <250 µeV, which yields a material that emits with a nearly constant rate over temperatures from 1.5 to 300 K and magnetic fields up to 7 T. The EI-manipulation strategies demonstrated here are general and can be applied to other nanostructures with variable electron-hole overlap.

Obesidad pregestacional y riesgo de intolerancia a la glucosa en el embarazo y diabetes gestacional / Pregestational obesity and risk of glucose intolerance in pregnancy and gestational diabetes

ANTECEDENTES: La obesidad en mujeres en edad reproductiva es cada vez más frecuente y complica el embarazo aumentando el riesgo de enfermedades como la diabetes mellitus gestacional (DMG). OBJETIVO: Determinar el riesgo de presentar DMG e intolerancia a la glucosa (ITG) de acuerdo con el índice de masa corporal pregestacional (IMCPG). MÉTODO: Muestra de 489 pacientes, se clasificaron por IMCPG y se les realizó una curva de tolerancia oral a la glucosa (CTOG) de 100 g de 120 minutos. Se definió DMG con dos valores alterados en la CTOG e ITG con un solo valor alterado. Se aplicó prueba de chi cuadrada para determinar diferencia entre grupos y se obtuvo un Odds Ratio (OR), con intervalo de confianza del 95%. RESULTADOS: 9 pacientes con bajo peso, 194 con peso normal, 158 con sobrepeso y 128 con obesidad, edad gestacional promedio 31,3 ± 5,6 semanas. El 13% de las pacientes presentaron DMG, el 10,6% ITG. Las mujeres con sobrepeso presentaron un OR de 3,81 para desarrollar ITG (IC95% 1,62-8,95) y un OR de 3,7 para DMG (IC95% 1,65-8,38), mientas que las pacientes con obesidad pregestacional presentaron un OR de 6,6 para desarrollar ITG (IC95% 2,83-15,66) y un OR de 8,8 para DMG (IC95% 4,05-19,51), comparadas con mujeres con peso pregestacional normal. CONCLUSIÓN: La población mexicana tiene mayor riesgo de DMG que otras poblaciones y mayor prevalencia de sobrepeso y obesidad, por lo que se debe realizar un diagnóstico y tratamiento oportuno de DMG, previniendo complicaciones y diabetes mellitus tipo 2.

BACKGROUND: Obesity in women in reproductive age is becoming more frequent and it self complicates preg-nancy increasing the risk of diseases such as gestational diabetes mellitus (GDM). AIMS: To determine the risk of gestational diabetes mellitus (GDM) and impaired glucose tolerance (IGT) according to the pregestational body mass index (PGBMI). METHODS: Sample of 489 patients, they were classified by PGBMI and underwent an oral glucose tolerance test (OGTT) with 100 g of glucose during 120 minutes. GDM was defined with two altered valúes in the OGTT and IGT with a single altered value. A chi-square test was applied to determine difference between groups, and we obtained an Odds Ratio (OR), with a confidence level of 95%. RESULTS: 9 patients were low weight, 194 normal weight, 158 overweight and 128 obese, average gestational age 31.3 ± 5.6 weeks. 13% of the patients had GDM, 10.6% had IGT. Overweight women had an OR of 3.81 of developing IGT (95% Cl 1.62-8.95) and an OR of 3.7 of developing GDM (95% Cl 1.65-8.38), while women with prepregnancy obesity showed an OR of 6.6 of developing ITG (95% Cl 2.83-15.66) and an OR of 8.8 of developing GDM (95% Cl 4.05-19.51), all compared to women with prepregnancy normal weight. CONCLUSIONS: Mexican population has a higher risk of GDM than other populations and also a higher prevalence of overweight and obesity, so that every pregnant woman should be screening for GDM, has a diagnosis and receive treatment, preventing complications and Type 2 Diabetes.

Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is characterised by recurrent infections of the upper respiratory airways (nose, bronchi, and frontal sinuses) and randomisation of left-right body asymmetry. To date, PCD is mainly described with autosomal recessive inheritance and mutations have been found in five genes: the dynein arm protein subunits DNAI1, DNAH5 and DNAH11, the kinase TXNDC3, and the X-linked retinitis pigmentosa GTPase regulator RPGR. METHODS: We screened 89 unrelated individuals with PCD for mutations in the coding and splice site regions of the gene DNAH5 by denaturing high performance liquid chromatography (DHPLC) and sequencing. Patients were mainly of European origin and were recruited without any phenotypic preselection. RESULTS: We identified 18 novel (nonsense, splicing, small deletion and missense) and six previously described mutations. Interestingly, these DNAH5 mutations were mainly associated with outer + inner dyneins arm ultrastructural defects (50%). CONCLUSION: Overall, mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients. Although genetic alterations remain to be identified in most patients, DNAH5 is to date the main PCD gene.

[Measles and its secondary pulmonary complications: prevention is better than treatment]. / Il morbillo e le sue complicanze polmonari secondarie: prevenire è meglio che curare.

Recent measles outbreaks observed in North America and in several European countries, including Italy, raised the attention about the risks linked to this infection and the need of implementing and maintaining adequate preventive strategies. Measles may cause several respiratory complications such as chronic obstructive lung disease, pneumonia, with subsequent development of chronic suppurative lung disease, giant cells pneumonia or progressive respiratory insufficiency. The current preventive strategies aim to improve vaccination coverage rates with 2 doses of measles-mumps and rubella vaccine, and to catch up individuals who have not been previously vaccinated. The present review analyses pulmonary complications of measles and measles preventive strategies. Elimination of measles is a feasible goal. Since measles complications are preventable by vaccination, improvement in vaccination coverage is highly desirable.

Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings.

In mucopolysaccharidoses, upper airway obstruction has multiple causative factors and progressive respiratory disease may severely affect morbidity and mortality. In a cross-sectional study over 2 years we evaluated upper airway obstructive disease through overnight polysomnography, upper airway computed tomography and nasal endoscopy in 5 children and 6 adults with mucopolysaccharidoses of various types. Measurements of apnoea and apnoea-hypopnoea index, arousal index, and sleep efficiency were obtained through polysomnography. Retropalatal and retroglossal spaces were calculated through computed tomography, and the degree of adenoid hypertrophy was assessed through endoscopy. Apnoea index and apnoea-hypopnoea index were significantly higher in children than in adults with mucopolysaccharidoses (p = 0.03 and p = 0.03, respectively). Compared to healthy controls, retropalatal and retroglossal spaces were significantly smaller in children (p = 0.03 and p = 0.004, respectively) or adults with mucopolysaccharidoses (p = 0.004 and p = 0.004, respectively). All subjects had adenoid hypertrophy causing first-degree (36%) or second-degree (64%) obstruction at endoscopy. Overnight polysomnography, upper airway computed tomography and nasal endoscopy are useful tools for diagnosing obstructive sleep apnoea syndrome in mucopolysaccharidoses, and identifying the site and severity of airway obstruction.