Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Predictivity of clinical efficacy of sublingual immunotherapy (SLIT) based on sensitisation pattern to molecular allergens in children with allergic rhinoconjunctivitis.

BACKGROUND: The diagnostic and therapeutic approach to grass pollen allergy is now possible by detecting specific IgE (sIgE) to its allergenic components. AIM: To evaluate the correlation between the sensitisation to different molecular Phleum pratense (Phl p) allergens and clinical efficacy of SLIT. METHODS: The pilot study included 36 patients affected by allergic rhinoconjunctivitis, all treated with SLIT actively. We performed serum analysis of sIgE to Phl p 1, 2, 4, 5, 6, 7, 11 and 12. The Average Rhinoconjunctivitis Total Symptom Score (ARTSS) and the Average Combined Score (ACS) were evaluated before and after one year of immunotherapy. RESULTS: Three different groups of sensitisation were defined based on the range of IgE reactivity to Phleum pratense allergens at baseline: group I (sIgE reactive to 1-3 allergens); group II (sIgE reactive to 4-5 allergens); and group III (sIgE reactive to 6-8 allergens). At T0 ACS was 1.79±0.18 in group I; 1.81±0.23 in group II; and 1.95±0.34 in group III. At T1 ACS was 0.85±0.55 in group I; 1.01±0.31 in group II; and 1.44±0.39 in group III. At T1 there was a significant improvement of ARTSS and ACS for group I (p=0.001). CONCLUSIONS: Sublingual immunotherapy with a grass pollen is efficacious irrespective of the patients' baseline sensitisation to either single or multiple grass pollen molecular allergens. We found that patients with few sensitisations have a greater improvement in combined symptom and medication score. SLIT improves the clinical course of allergic patients although new sensitisations may appear.

De novo transcriptome assembly of sugarcane leaves submitted to prolonged water-deficit stress.

Sugarcane production is strongly influenced by drought, which is a limiting factor for agricultural productivity in the world. In this study, the gene expression profiles obtained by de novo assembly of the leaf transcriptome of two sugarcane cultivars that differ in their physiological response to water deficit were evaluated by the RNA-Seq method: drought-tolerant cultivar (SP81-3250) and drought-sensitive cultivar (RB855453). For this purpose, plants were grown in a greenhouse for 60 days and were then submitted to three treatments: control (-0.01 to -0.015 MPa), moderate water deficit (-0.05 to -0.055 MPa), and severe water deficit (-0.075 to -0.08 MPa). The plants were evaluated 30, 60, and 90 days after the beginning of treatment. Sequencing on an Illumina platform (RNA-Seq) generated more than one billion sequences, resulting in 177,509 and 185,153 transcripts for the tolerant and sensitive cultivar, respectively. These transcripts were aligned with sequences from Saccharum spp, Sorghum bicolor, Miscanthus giganteus, and Arabidopsis thaliana available in public databases. The differentially expressed genes detected during the prolonged period of water deficit permit to increase our understanding of the molecular patterns involved in the physiological response of the two cultivars. The tolerant cultivar differentially expressed a larger number of genes at 90 days, while in the sensitive cultivar the number of differentially expressed genes was higher in 30 days. Both cultivars perceived the lack of water, but the tolerant cultivar responded more slowly than the sensitive cultivar. The latter requires rapid activation of different water-deficit stress response mechanisms for its survival. This rapid activation of metabolic pathways in response to water stress does not appear to be the key mechanism of drought tolerance in sugarcane. There is still much to clarify on the molecular and physiological pattern of plants in response to drought.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).

The wolf in sheep's clothing: Microtomographic aspects of clinically incipient radiation-related caries.

BACKGROUND: Radiation related caries (RRC) can cause rapid progression, with a high potential for dental destruction affecting mainly cervical and incisal areas. Unlike the injuries that occur in the conventional caries, incipient RRC present in unusual surfaces have difficult diagnosis and classification stages of cavitation. MATERIAL AND METHODS: Evaluate the radiographic patterns of demineralization of RRC by using micro-CT. Ten teeth with incipient RRC and 10 teeth with incipient conventional caries (control group) matched by anatomic teeth group and caries affected surfaces were evaluated by X-ray microtomography (micro-CT) Skyscan 1174V2 (50Kv, 1.3 megapixel, Kontich, Belgium). Teeth were placed in a standard position for micro-CT (coronal, transaxial and sagittal sections) during images acquisition. Lesions were classified according to the depth of invasion and relationship with enamel, dentin and pulp. RESULTS: RRC samples presented deeper lesions with higher involvement of enamel and dentin. Control group presented focal and superficial lesions with lower involvement of enamel and dentin. CONCLUSIONS: Incipient RRC present aggressive microtomographic patterns of demineralization when compared to conventional caries, as indicated by deep lesions, regardless of its clinically incipient aspects.

Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN).

A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.

Risk factors affecting quality of life in a group of Italian children with asthma.

The measure of Quality of Life (QoL) has become one of the most important criteria used to assess the impact of chronic illness, such as asthma, on the patient’s daily life, in adults and children alike. The objective of our open observational study was to measure the QoL and analyze several factors that potentially affect QoL, such as symptoms and functional respiratory parameters, in a cohort of children with asthma. One hundred and twenty-seven children with asthma, 6 to 14 years of age, living in the city of Rome, were enrolled as outpatients. They were subjected to Skin Prick Tests (SPT), underwent spirometry and filled out the Pediatric Asthma Quality of Life Questionnaire (PAQLQ). One hundred and eleven children were diagnosed with intermittent asthma, 12 (10%) with mild asthma, and four with moderate persistent asthma. Ninety-six children had a positive SPT. The mean total score of QoL, obtained from the questionnaire, was 5.4 (∓1.2 SD). Two QoL groups were created. Children with total QoL score <5.5 were included in the “Lower QoL” score group while children with total QoL score ≥ 5.5 were included in the “Higher QoL” score group. Children in the Higher group and their mothers had a higher mean age, suffered from fewer asthma exacerbations during the year preceding the study, and showed a higher mean value of forced expiratory volume (FEV1) compared to the children in the Lower category. Using Logistic regression we identified the main factors that may affect QoL as FEV1, symptoms in the previous year and mother’s age. QoL is correlated with the frequency of asthma exacerbations and FEV1 values. Furthermore, our research shows that a significant impairment of QoL may also occur in patients with normal lung function, pointing out the importance of evaluating QoL in all children with asthma.

Serum resistin levels in children with primary snoring.

Primary Snoring (PS) has been positioned at the milder end of the Sleep-Disordered Breathing severity continuum characterized by snoring and it is usually underestimated. PS is defined as snoring without apnea, frequent arousals, or gas exchange abnormalities and recent studies demonstrated that children with PS have increased blood pressure and reduced arterial distensibility. The association between adipokines and SDB has been recently investigated, though most of the studies were focused on OSAS where intermittent hypoxia characterizing the disease may lead to an inflammatory cascade and to the release of several adipokines, contributing to oxidative stress. Resistin, initially described s an adipokine increasing insulin resistance, has been recently identified as a novel important member of the cytokine family involved in the regulation of inflammation. The aim of our study was to investigate circulating resistin levels in normal weight children with PS. Sixty-five children of normal weight aged between 4 and 14 years of age were selected for habitual snoring. Children with positive polysomnography were excluded from the study. Serum resistin levels were detected in all children with PS. Thirty-three healthy non-snorer children with similar age, sex and BMI were selected as a control group. A significantly higher level of resistin was observed in patients with PS compared to the control group (4.67±1.91 ng/ml vs 3.98±1.58 ng/ml; p<0.01). Patients with inconclusive pulse oximetry showed significantly higher resistin levels than those with negative recordings recordings (5.29±1.91 ng/ml vs 4.20±1.93 ng/ml; p<0.008). Moreover, there was a significant increasing trend between sieric adipokine level and the frequency of snoring (p<0.006). Our results suggest that systemic inflammation and oxidative stress may also play a significant role in the pathophysiology of PS.

Habitual snoring in children with previous allergic sensitization.

Previous studies have reported a high prevalence of allergy in children with Habitual Snoring (HS), but the relationship between allergy in the early years of life and the subsequent development of this Sleep Disordered Breathing (SDB) is yet to be elucidated. The purpose of the present study was to determine the role of early, under 36 months of age, allergic sensitization to food (with or without sensitization to airborne allergens) in determining the development of HS 8-10 years after. One hundred and forty-eight children (10-14 years, mean age 12 years) with a history of food allergy were selected. Under the age of 36 months, atopic status was assessed by skin prick test for a panel of airborne and food allergens. Questionnaires filled in by parents were used to collect information on children's snoring and associated symptoms. HS was defined as snoring three or more times per week. At 1-3 years of age 54 children were positive to food allergens alone, and 94 were positive also to airborne allergens. After 8-10 years of life, when patients were aged between 10 and 14 years, habitual snoring was reported in 37 children. Furthermore, among the 54 children under three years of age sensitized only to food, 8 became HS while of the 94 children sensitized to both food and inhalants allergens 29 developed HS. The difference between those two groups was statistically significant (p=0.04). We reported a significant risk of developing HS in children with early allergic sensitization. Specifically this risk was higher when food allergy was associated with inhalant allergy. The onset of upper airway inflammation due to allergic triggers in subjects under three years of age may be related to the subsequent development of SDB after 8-10 years.

Efficacy of sublingual specific immunotherapy on allergic asthma and rhinitis in children's real life.

BACKGROUND: Sublingual-specific immunotherapy (SLIT) is considered as a valid treatment of respiratory allergies. AIM: We performed a case-control study to evaluate the effect of SLIT in children with allergic asthma and rhinitis. PATIENTS AND METHODS: The study plan included 140 patients (age 6-14 yr, 43% girls and 57% boys) presenting allergic rhinitis and/or asthma, 70 treated with SLIT actively for three years and 70 controls never treated with specific immunotherapy (only symptomatic drugs). Rhinitis Symptom Score (RSS), Asthma Symptom Score (ASS) and Medication Score (MS) were evaluated at beginning and during the 3 years of immunotherapy. results: There was a significant improvement of RSS (mean ± SD) in the SLIT group: baseline 5.31 ± 2.01, third year 1.38 ± 1.06 (p < 0.0001 vs baseline). CONTROL GROUP: baseline 5.00 ± 1.08, third year 4.68 ± 1.152 (P » NS). ASS (mean ± SD) in the SLIT group: baseline 4.09 ± 2.21, third year 1.23 ± 1.4 (p < 0.0001 vs baseline). CONTROL GROUP: baseline 4.04 ± 2.46, third year 3.62 ± 2.26 (p » NS). MS (mean ± SD) in the SLIT group: baseline 3.30 ± 1.4, third year 0.88 ± 1.26 (p < 0.0001 vs baseline). CONTROL GROUP: baseline 3.19 ± 1.23, third year 3.39 ± 1.12 (p » NS). There are no statistically significant differences among monosensitized/polysensitized patients and at different age ranges. None of the patients included reported severe systemic reactions or anaphylaxis. CONCLUSIONS: During the treatment, the active group showed sustained reductions in mean asthma and rhinitis symptom scores when compared with controls to confirm the efficacy and safety of sublingual immunotherapy.

Food allergy and the development of asthma symptoms.

Allergies are multifactorial diseases the onset of which depends also on genetic and environmental factors in early life. Thus, environmental factors can affect the immune response and modify lung development, thereby leading to asthma. The role of the factors used to date to predict asthma development is modest, and clinical criteria should always be considered in association with familiarity for atopy. The aim of this study is to evaluate the risk of asthma in a population with positive skin prick test (SPT) (which is a reliable marker of atopy) to food allergens, regardless of clinical manifestations in the early years of life. The cohort of children enrolled in our study who had a positive SPT to food in the first three years of life had a prevalence of asthma after 7-14 years, double that of the general pediatric population. This prevalence increased significantly in patients with SPT positivity for food and inhalant allergens. We identified a correlation between the sensitization profile in children under the age of 36 months and the development of asthma during a period of 7-14 years. This study confirms that early sensitization is an important risk factor for the development of asthma, particularly in association with sensitization to inhalants, and that the persistence of food sensitization in school-age children and adolescents is associated to more severe asthma.

What triggers phenological events in plants under seasonal environments? A study with phylogenetically related plant species in sympatry.

In this study, we evaluated variation in vegetative and reproductive phenological events of four phylogenetically related plant species subjected to a seasonal environment. To this aim, we sampled 15 individuals of each plant species every fortnight for one year, between January and December of 2017. To assess when a given phenophase occurred more intensely in the population, the Fournier intensity index was used and the synchrony of individuals of the sample in a given phenological event was estimated using the activity index. The Rayleigh (Z) test was used to determine whether the phenological events have seasonal distribution. The relationship of abiotic factors (photoperiod, precipitation, relative humidity and temperature) with the intensity of phenophases was evaluated for each plant species using generalized linear models (GLMs). The phenophases of all plants showed a seasonal distribution pattern, as well as variation in synchrony of phenophases and specific sets of abiotic factors significantly influenced their phenophases. New leaves, for example, were produced throughout the seasons, with intense leaf fall in the dry season. Flowering periods, on the other hand, did not overlap. Indeed, species exhibited sequential flowering and asynchronous flowering among individuals. Our results suggest that the phenological patterns of four sympatric plant species are directly linked to climatic variables, but different abiotic factors affected different phenophases.

Weight loss induced by 6-month lifestyle intervention improves early endothelial activation and fibrinolysis in obese adolescents.

BACKGROUND: Adolescent obesity is associated with an increased risk of adult obesity and subsequent cardiovascular diseases. The present study aimed to assess the effect of weight loss after 6-month lifestyle intervention in obese adolescents on biomarkers of endothelial activation and fibrinolytic system. METHODS: Eighty-five obese adolescents aged 10 to 16 years were assigned to a 6-month lifestyle intervention and 61 completed the programme. We examined the effect of the intervention on adhesion molecules (selectin E, soluble intercellular adhesion molecule 1 and soluble vascular adhesion molecule 1) and fibrinolytic parameters [plasminogen activator inhibitor-1 (PAI-1) and fibrinogen]. Thirty-six lean adolescents were studied only at baseline as a comparison group. RESULTS: Compared with lean participants, obese adolescents at baseline demonstrated significantly higher levels of triglycerides, glucose, insulin, homeostasis model assessment, soluble intercellular adhesion molecule 1, PAI-1 and fibrinogen. After 6-month lifestyle intervention, those obese adolescents with decreased standard deviation score-body mass index (SDS-BMI) displayed significant decreases in insulin (19.2 ± 11.2 vs. 26.8 ± 13.2 mU/L, P≤ 0.01), homeostasis model assessment (4.24 ± 3.19 vs. 6.58 ± 4.08, P≤ 0.01), selectin E (100.2 ± 60.9 vs. 116.0 ± 69.0 ng/mL, P≤ 0.01) and PAI-1 (39.6 ± 38.0 vs. 51.8 ± 25.6 ng/mL, P≤ 0.05) with respect to the baseline levels. No changes in these parameters were observed in the obese adolescents with stable or increased SDS-BMI. The changes of triglycerides after intervention in subgroup with decreased SDS-BMI were significantly greater than those in subgroup with stable SDS-BMI. CONCLUSIONS: The present study demonstrated increased endothelial activation and impairment of the fibrinolytic system in early life, which is in part reversible by a 6-month lifestyle intervention.

A DFT investigation of lithium adsorption on graphenes as a potential anode material in lithium-ion batteries.

We present a detailed study of the Li+ ion adsorption on two different hydrogenated carbon nanostructures, namely as pristine graphene (PG) and topologic Stone-Wales defective graphene (SWG) using the density functional theory (DFT). The studies are focused to analyze the structure-stability relationship with the estimated electronic and electrical properties for lithium-ion batteries (LIB) formed with an anode based on the Li/Li+#PG and Li/Li+#SWG systems. In addition, the electronic effects induced due to Li+ adsorption and the presence of SW defect on the graphene models were analyzed by the frontier molecular orbitals, ChelpG charges, Raman and UV-Vis spectra. It was verified that Li+ is more stably adsorbed on the edges on both graphene structures through an electrostatic interaction between cation and more negatively charged edges of nanostructures. TD-DFT calculations showed that the metallic nature of isolated graphene is disturbed after the adsorption of Li+, and this was demonstrated from the calculated HOMO-LUMO gap. The same Li+-Graphene geometries were optimized by introducing neutral charge in order to enable the calculation of ionization potentials. I was also found that such systems potentially contributed to the modeling of graphene-based anodes with reasonable electrical voltage responses estimated for a LIB. The simulation of Raman and UV-Vis spectra revealed significant variations in intensity and shifts the typical bands of graphene due to the presence of the Li+ ion that can contribute to point out new experiments to the spectroscopic characterization of these systems. Our results suggest that these carbon nanostructures are potential candidates for efficient applications in electrochemical systems, mainly dealing with LIB.

Flare-up of hand osteoarthritis caused by zoledronic acid infusion.

Zoledronic acid is effective for osteoporosis at a single annual intravenous dose. It usually causes few adverse effects; the most common are related to acute phase reactions. We reported the case of a 64-year-old woman who presented flare-up of hand osteoarthritis after zoledronic acid infusions. Despite the fact that arthralgia is a common side effect of intravenous bisphosphonates, development of inflammatory signs in osteoarthritic joints is a rare event. We hypothesized that this side effect is caused by a release of cytokines secondary to activation of gamma-delta T lymphocytes.

Risk factors for upper airway diseases.

Upper respiratory infection is the most common reason for seeking medical care for children. Recurrent viral respiratory infections and subsequent complications are a burden for children, their families and society. It has been estimated that at least 6 percent of children younger than 6 yr of age presents recurrent respiratory infections, as consequence of an increased exposure to infectious agents during the first years of life, when immune functions are still immature. Pediatricians must identify risk factors predisposing to upper respiratory tract infections and plan specific preventive strategies, ie avoidance of precocious day-care attendance and secondary smoke. Vaccination against influenza and pneumococcal diseases should always be recommended.

An infant with diaphragmatic eventration and respiratory distress.

The authors report a rare case of partial diaphragmatic eventration in a 4-month-old infant with recurrent wheezing and low serum IgA values. Because of persistent respiratory symptoms after therapy with inhaled short-acting beta2 agonists and inhaled nebulized corticosteroids, surgery was undertaken to correct the defect. Despite surgery, the clinical symptoms did not improve. Consequently, gatroesophagel reflux was considered and the diagnosis was confirmed with pH-metry, after which the infant was started on a protonic pump inhibitor therapy (PPI), achieving clinical improvement. Our experience suggests that in infants with congenital diaphragmatic eventration who present with respiratory distress gastro-oesophageal reflux should be suspected, and PPI therapy should be started before planning surgery.

What triggers phenological events in plants under seasonal environments? A study with phylogenetically related plant species in sympatry / O que desencadeia eventos fenológicos em plantas em ambientes sazonais? Um estudo com espécies de plantas filogeneticamente relacionadas e em simpatria

In this study, we evaluated variation in vegetative and reproductive phenological events of four phylogenetically related plant species subjected to a seasonal environment. To this aim, we sampled 15 individuals of each plant species every fortnight for one year, between January and December of 2017. To assess when a given phenophase occurred more intensely in the population, the Fournier intensity index was used and the synchrony of individuals of the sample in a given phenological event was estimated using the activity index. The Rayleigh (Z) test was used to determine whether the phenological events have seasonal distribution. The relationship of abiotic factors (photoperiod, precipitation, relative humidity and temperature) with the intensity of phenophases was evaluated for each plant species using generalized linear models (GLMs). The phenophases of all plants showed a seasonal distribution pattern, as well as variation in synchrony of phenophases and specific sets of abiotic factors significantly influenced their phenophases. New leaves, for example, were produced throughout the seasons, with intense leaf fall in the dry season. Flowering periods, on the other hand, did not overlap. Indeed, species exhibited sequential flowering and asynchronous flowering among individuals. Our results suggest that the phenological patterns of four sympatric plant species are directly linked to climatic variables, but different abiotic factors affected different phenophases.

Neste estudo, avaliamos a variação nos eventos fenológicos vegetativos e reprodutivos de quatro espécies de plantas filogeneticamente relacionadas submetidas a um ambiente sazonal. Para isso, amostramos 15 indivíduos de cada espécie quinzenalmente, pelo período de um ano, entre janeiro e dezembro de 2017. Para avaliar quando uma determinada fenofase ocorreu de modo mais intenso na população foi utilizado o índice de intensidade de Fournier e a sincronia dos indivíduos da amostra em determinado evento fenológico foi estimada utilizando-se o índice de atividade. O teste de Rayleigh (Z) foi usado para determinar se os eventos fenológicos têm distribuição sazonal. A relação dos fatores abióticos (fotoperíodo, precipitação, temperatura e umidade relativa) com a intensidade das fenofases foi avaliada para cada espécie de planta usando modelos lineares generalizados (GLMs). As fenofases de todas as plantas apresentaram um padrão de distribuição sazonal, bem como variação na sincronia das fenofases e conjuntos específicos de fatores abióticos influenciaram significativamente suas fenofases. Folhas novas, por exemplo, foram produzidas ao longo das estações, com intensa queda de folhas na estação seca. Os períodos de floração, por outro lado, não se sobrepuseram. De fato, as espécies exibiram floração sequencial e floração assíncrona entre os indivíduos. Nossos resultados sugerem que os padrões fenológicos das quatro espécies de plantas simpátricas estão diretamente ligados às variáveis climáticas, mas diferentes fatores abióticos afetaram diferentes fenofases.