Combined PIK3CA and SOX2 Gene Amplification Predicts Laryngeal Cancer Risk beyond Histopathological Grading.

The PIK3CA and SOX2 genes map at 3q26, a chromosomal region frequently amplified in head and neck cancers, which is associated with poor prognosis. This study explores the clinical significance of PIK3CA and SOX2 gene amplification in early tumorigenesis. Gene copy number was analyzed by real-time PCR in 62 laryngeal precancerous lesions and correlated with histopathological grading and laryngeal cancer risk. Amplification of the SOX2 and PIK3CA genes was frequently detected in 19 (31%) and 32 (52%) laryngeal dysplasias, respectively, and co-amplification in 18 (29%) cases. The PIK3CA and SOX2 amplifications were predominant in high-grade dysplasias and significantly associated with laryngeal cancer risk beyond histological criteria. Multivariable Cox analysis further revealed PIK3CA gene amplification as an independent predictor of laryngeal cancer development. Interestingly, combined PIK3CA and SOX2 amplification allowed us to distinguish three cancer risk subgroups, and PIK3CA and SOX2 co-amplification was found the strongest predictor by ROC analysis. Our data demonstrate the clinical relevance of PIK3CA and SOX2 amplification in early laryngeal tumorigenesis. Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

Ion Channel Dysregulation in Head and Neck Cancers: Perspectives for Clinical Application.

Head and neck cancers are a highly complex and heterogeneous group of malignancies that involve very diverse anatomical structures and distinct aetiological factors, treatments and clinical outcomes. Among them, head and neck squamous cell carcinomas (HNSCC) are predominant and the sixth most common cancer worldwide with still low survival rates. Omic technologies have unravelled the intricacies of tumour biology, harbouring a large diversity of genetic and molecular changes to drive the carcinogenesis process. Nonetheless, this remarkable heterogeneity of molecular alterations opens up an immense opportunity to discover novel biomarkers and develop molecular-targeted therapies. Increasing evidence demonstrates that dysregulation of ion channel expression and/or function is frequently and commonly observed in a variety of cancers from different origin. As a consequence, the concept of ion channels as potential membrane therapeutic targets and/or biomarkers for cancer diagnosis and prognosis has attracted growing attention. This chapter intends to comprehensively and critically review the current state-of-art ion channel dysregulation specifically focusing on head and neck cancers and to formulate the major challenges and research needs to translate this knowledge into clinical application. Based on current reported data, various voltage-gated potassium (Kv) channels (i.e. Kv3.4, Kv10.1 and Kv11.1) have been found frequently aberrantly expressed in HNSCC as well as precancerous lesions and are highlighted as clinically and biologically relevant features in both early stages of tumourigenesis and late stages of disease progression. More importantly, they also emerge as promising candidates as cancer risk markers, tumour markers and potential anti-proliferative and anti-metastatic targets for therapeutic interventions; however, the oncogenic properties seem to be independent of their ion-conducting function.

First report of Fusarium clavum causing garlic bulb rot in Mexico.

In Mexico, the main states for garlic (Allium sativum L.) production are Zacatecas, Guanajuato, and Puebla. In the 2020 crop season, garlic cultivation encompassed 6,794 ha, yielding 85,505 tons (SIAP, 2021). In February 2020, 35 garlic samples showing basal rot symptoms were collected from the garlic-growing regions in the states of Zacatecas and Aguascalientes in the municipalities of San Antonio Tepezala 22°13'13.5''N, 102°15'55.3''W, Rincón de Romos 22°17'44.9''N, 102°13'06.8''W, and Calera 22°58'39.4''N and 102°41'29.9W, respectively. The sampling carried out was random sampling by conglomerates, dividing each field in groups with plants that showed similar symptoms. The infected plants were stunted in growth, with reddish dying leaves. The stalks and bulbs were soft, and their root system was poorly developed. The collected samples were placed in polyethylene bags and taken to laboratory. The roots and bulbs of 35 plants were cleaned, portions of the diseased tissue was cut into 0.5 cm pieces and disinfected in 1% sodium hypochlorite for 3 minutes. The samples were rinsed twice with sterile distilled water and dried on sterile paper towels. The tissues were cultured on Potato Dextrose Agar (PDA) medium and incubated in the dark at 25°C. Seven days after incubation, pure cultures were obtained using monoconidial cultures technique on Spezieller Nährstoffmmarmer agar (SNA) and subcultured on carnation leaf agar (CLA). Ten isolates were obtained that grew slowly, showing a white coloration, then turning yellow with abundant aerial mycelia. Microscopic traits of 30 characterized spores included slender macroconidia that were curved dorsiventrally, tapering towards both ends, with five to seven thin septa, measuring 36.4-56.6 µm × 4.0-4.9 µm in size and chlamydospores that were abundant, globose to oval, subhyaline and terminal or intercalary in chains measuring 8.8-4.5 µm in diameter. Microconidia, were single-celled, hyaline, nonseptate, and ovoid. The morphological traits matched the description of Fusarium clavum (Xia et al. 2019). To confirm the strain's identity, DNA was extracted from six monoconidial cultures and used as template to amplify translation elongation factor (TEF) gene 1α, RNA polymerase largest subunit (RPB1), and RNA polymerase second largest subunit (RPB2) (O'Donnell et al. 2010). The products were sequenced and deposited in GenBank as ON209360, OM640008 and OM640009, the homology analysis using BLASTn was similar to F. clavum with 99.46%, 99.49% and 98.82% respectively with E VALUE 0.0 in all cases with access numbers OP48709, HM347171 and OP486686. Koch postulate was performed to confirm the pathogenicity of the six isolates. Variegated garlic cloves were planted after being disinfected with sodium hypochlorite at 3% w/v in 2-kg pots under the greenhouse conditions. When the garlic plants developed 4 or 5 true leaves, their basal stalks were inoculated by pouring uniformly with 1 mL of a spore suspension at 108 conidia/mL prepared from 1-week-old colonies (Lai et al. 2020). Twenty-four plants were inoculated with six isolates (four plants per isolate), and four control plants were treated with sterile distilled water. Symptoms appeared 20 days post-inoculation. The leaves were reddish, and the stalks were soft. The leaves eventually developed foliar dieback disease symptoms, their root system showed brown lesions and rot, and all water-inoculated controls remained asymptomatic. Isolations were made on the diseased plants, and the inoculated pathogen was recovered and confirmed morphologically and molecularly by DNA extraction and PCR reactions. Koch's postulate was repeated twice, obtaining the same results. To our best knowledge, this is the first report of F. clavum infecting Allium sativum L. in Mexico. bulb rot caused by F. clavum is a severe threat to garlic cultivation, and identification of this pathogen is important for effective disease management and control.

The influence of meaningful activities in the quality of life and functional autonomy of adults with intellectual disability: A prospective study during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic might negatively impact the quality of life and functional autonomy of Spanish adults with intellectual disability, and meaningful activities could prevent this negative progression. METHODS: This is a prospective cohort study in Spanish adults with intellectual disability during the COVID-19 pandemic. Quality of life, functional autonomy and functional independence were measured. The meaningful activities studied were structured-leisure, community self-management, and occupational and physical activities. RESULTS: Seventy-three participants were included in the study. Quality of life and functional autonomy significantly deteriorated during the COVID-19 pandemic (all p > .001). Greater participation in community self-management activities before COVID-19 was associated with less detriment to quality of life (ß = -.312; p = .008), while greater participation in occupational and physical activities was associated with less detriment to the performance of instrumental activities (ß = -.317; p = .016; and ß = -.285; p = .030, respectively). CONCLUSION: People with intellectual disability living in residential homes experienced a decrease in their quality of life and functional autonomy during the COVID-19 pandemic. Their involvement in community self-management activities and physical and occupational activities before the pandemic had preventive effects on the detriment to the quality of life and functional autonomy.

The cytoplasmic microtubule array in Neurospora crassa depends on microtubule-organizing centers at spindle pole bodies and microtubule +end-depending pseudo-MTOCs at septa.

γ-Tubulin ring complexes (γ-TuRC) mediate nucleation and anchorage of microtubules (MTs) to microtubule organizing centers (MTOCs). In fungi, the spindle pole body (SPB) is the functional equivalent of the centrosome, which is the main MTOC. In addition, non-centrosomal MTOCs (ncMTOCs) contribute to MT formation in some fungi like Schizosaccharomyces pombe and Aspergillus nidulans. In A. nidulans, MTOCs are anchored at septa (sMTOC) and share components of the outer plaque of the SPB. Here we show that the Neurospora crassa SPB is embedded in the nuclear envelope, with the γ-TuRC targeting proteins PCP-1Pcp1/PcpA located at the inner plaque and APS-2Mto1/ApsB located at the outer plaque of the SPB. PCP-1 was a specific component of nuclear MTOCs, while APS-2 was also present at the septal pore. Although γ-tubulin was only detected at the nucleus, spontaneous MT nucleation occurred in the apical and subapical cytoplasm during recovery from benomyl-induced MT depolymerization experiments. There was no evidence for MT nucleation at septa. However, without benomyl treatment MT plus-ends were organized in the septal pore through MTB-3EB1. Those septal MT plus ends polymerized MTs from septa in interphase cells Thus we conclude that the SPB is the only MT nucleation site in N. crassa, but the septal pore aids the MT network arrangement through the anchorage of the MT plus-ends through a pseudo-MTOC.

Effective access to health care in Mexico.

OBJECTIVES: This paper assesses the impact of effective access on out-of-pocket health payments and catastrophic health expenditure. Effective access cannot be attained unless both health services and financial risk protection are accessible, affordable, and acceptable. Therefore, it represents a key determinant in the transition from fragmented health systems to universal coverage that many low- and middle-income countries face. METHODS: We use a definition of effective access as the utilization of health insurance when available. We conducted a cross-sectional analysis using the 2018 Mexican National Health Survey (ENSANUT) at the household level. The analysis is performed in two stages. The first stage is a multinomial analysis that captures the factor associated with choosing effective access against the alternative of paying privately. The second stage consists of an impact analysis regarding the decision of not choosing effective access in terms of out-of-pocket (OOP) health payments and catastrophic health expenditures (CHE). The analysis corrects for both the decision to buy insurance and the decision to pay for health care. RESULTS: We found that, on average, not choosing effective access increases OOP health payments by around 2300 pesos annually. Medicine payments are the most common factor in this increase. Nevertheless, outpatient and medicines health care are the main drivers of the increase in OOP health payments in all insurance beneficiaries. Not having effective access increases the probability of CHE health expenditures by 2.7 p.p. for the case of Social Security Insurance and 4.0 p.p. for Social Government insurance. Household enrolled in Prospera program for the poor are more likely to choose effective access while having household heads with more education and assets value does the opposite. Diabetes illnesses are associated with a higher probability of effective access. CONCLUSION: Improving effective access is a middle step that cannot be disregarded when seeking universal coverage because OOP health payments and catastrophic outcomes are direct consequences. Public insurance in general, has around 50% effective access which remains a challenge in terms of health services utilization and health public policy design, calling for the need of better coordination across insurance types and pooling mechanisms to increase sustainability of needed health services.

First report of Clonostachys rosea causing root rot on garlic in Mexico.

Garlic (Allium sativum) is an important crop worldwide and it is widely grown and used in different industries to manufacture food, pharmaceutical, and insecticidal products. (Shang et al., 2019, Velsankar et al., 2020). According to what was reported by SIAP in 2020, more than 87 ha of the crop were lost in Mexico due to various problems, including the diseases that attack this crop such as basal rot, white rot and root rot, among others. During the 2019 fall/winter season, garlic plants of Perla and Piedra Blanca cultivars were collected from Aguascalientes and Zacatecas states in San Antonio Tepezala, Rincon de Romos, and Calera municipalities. The commercial fields encompassed 10 ha with 20% disease incidence and 35% severity, approximately. The sampling focused on diseased plants with symptoms of root rot, foliar wilt, stunting, and small bulbs. The roots of 25 plants were cleaned, and portions of the diseased tissue were cut and disinfected in sodium hypochlorite at 1% for three minutes. They were rinsed twice with sterile water and dried with paper towels. The plant tissue was plated onto potato dextrose agar (PDA) and incubated at 25°C in the dark for 72 hours. Pure cultures were obtained after observing mycelial growth using monosporal culture. We obtained 16 isolates including three identified as Fusarium oxysporum, one as Fusarium solani and another 12 as Clonostachys rosea. The latter isolates were white at the beginning before turning yellow. The mycelia had a felt-like cotton texture. The conidia formed verticillate and penicillate conidiophores. The primary conidia were abundant, hyaline, smooth, and sub-globous. They were 5.1-7.7 X 8.3-8.9 µm (n=50) long and 2.0-2.9 X 3.2-3.5 µm wide (n=50). The conidiophore stipe length ranged from 70 to 180 µm, and the base width was 3.3-5.4 µm. Secondary conidiophores were penicillate and stiped with a length of 58 to 106 µm; the base measured 3.3-6.1µm. The secondary conidia measured 4.1-5 X 5.3-5.6 µm long and 2-2.3 X 2.6-2.9 µm wide (n=50) (Sun et al., 2020). The identity of six isolates was molecularly confirmed by DNA extraction and PCR reactions using ITS1/ITS4 primers and gene TEF 1α EF1-728F/TEF 1α EF1-986R. The resulting products were sequenced and compared with the National Center for Biotechnology Information (NCBI) database using BLAST. The results showed Clonostachys rosea at 99.56 and 100% with access numbers MN548399 and KX185000. The sequences were deposited at Genbank database under access number OK263088 and OL700031. Pathogenicity tests were carried out with the following procedure. A conidial suspension of five isolates (5×105 conidia/ml) in sterilized water was prepared from 1-week-old colonies. The garlic cloves were planted after being disinfected with sodium hypochlorite at 1% in sterilized soil. When the healthy garlic plants were 30 days old, we inoculated a spore suspension in soil through irrigation, to 10 plants. Likewise,10 control plants were inoculated with sterile distilled water. After 25 days, the plants were wilted and had dry leaves; their root system showed light-brown lesions and rot. These plants were stunted versus the control healthy plants. The inoculated strain was recovered and was morphologically and molecularly identified as C. rosea, thus confirming its pathogenicity towards garlic. There are reports of C. rosea causing root rot to Fabaceae crops such as Glycine max L. and Vicia faba L., (Bienapfl et al., 2012; Afshari and Hemmati, 2017) in addition to affecting orchid crops (Gastrodia elata) in Korea (Lee et al., 2020). This is the first report of C. rosea causing root rot on garlic (Allium Sativum) in Mexico, thus presenting a potential risk to this crop.

Tailored modulation of the inflammatory balance in COVID-19 patients admitted to the ICU?-a viewpoint.

A growing consensus seems to be emerging that dexamethasone is a crucial component in the treatment of COVID-19-associated oxygen-dependent respiratory failure. Although dexamethasone has an undeniably beneficial effect on the inflammatory response in a subgroup of patients, the potential negative effects of corticosteroids must also be considered. In view of these negative effects, we argue that a one-size-fits-all dexamethasone approach may be potentially harmful in specific subsets of patients with COVID-19-associated ARDS. We propose a different individually tailored treatment strategy based on the patient's inflammatory response.

PD-L1 expression correlates with tumor-infiltrating lymphocytes and better prognosis in patients with HPV-negative head and neck squamous cell carcinomas.

INTRODUCTION: The importance of immune tumor microenvironment in the prognosis of patients with head and neck squamous carcinomas (HNSCC) is increasingly recognized. We analyzed the prognostic relevance of PD-L1 and PD-1 expressions in relation to the infiltration by CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs). METHODS: Samples from 372 surgically treated HPV-negative HNSCC patients were evaluated by immunohistochemistry for PD-L1 expression [both tumor proportion score (TPS) and combined proportion score (CPS)], PD-1 expression in immune cells, and density of infiltrating CD8+ and FOXP3+ TILs. PD-L1 expression and CD8+ TIL density were combined to establish the type of tumor microenvironment. RESULTS: 29.5% cases exhibited PD-L1 TPS positivity (≥ 1%), whereas PD-L1 CPS positivity (≥ 1%) was observed in 40% cases. 47.5% cases showed positive PD-1 expression (≥ 1%). PD-L1 and PD-1 positivity correlated with a high density of both CD8+ and FOXP3+ TILs. In univariate analysis, PD-L1 TPS positivity (P = 0.026), PD-L1 CPS positivity (P = 0.004), high density of CD8+ TIL (P = 0.001), and high density of FOXP3+ TIL (P = 0.004) were associated with a better disease-specific survival (DSS). However, in multivariate analysis, only high density of CD8+ TIL was associated with a better DSS (P = 0.002). The type of tumor microenvironment correlated with DSS (P = .008), with the better DSS observed in cases with type I (PD-L1 CPS positivity and high density of CD8+ TIL). CONCLUSIONS: High infiltration by CD8+ TIL is associated with better survival outcomes. Positive PD-L1 expression correlates with a high infiltration by TILs, explaining its association with better prognosis.

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib.

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer.Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC.Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples.Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer.Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.

Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study.

To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS ≥ 70%, MGMT methylation, lower stage, and tumor ≤ 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001)-but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved.

Obstetric and neo-natal outcomes of ICSI cycles using pentoxifylline to identify viable spermatozoa in patients with immotile spermatozoa.

Pentoxifylline (PF) represents an effective tool in stimulating motility and identifying viable spermatozoa in intracytoplasmic sperm injection (ICSI) patients presenting exclusively with immotile spermatozoa. However, its use is not universally accepted for its possible detrimental effects on oocytes, embryos or newborns. To evaluate whether PF use may affect obstetrical/neo-natal outcomes, 102 patients achieving a clinical pregnancy after a PF-ICSI in four IVF units in Spain and Italy were followed up after delivery. Neo-natal malformations were classified according to the World Health Organization International Classification of Diseases (ICD-10, range Q00-Q99). Malformation rate was compared with data published by other groups regarding children conceived by conventional IVF or ICSI reporting a 5.3% and 4.4% frequency of ICD-10 codes, respectively. Of 134 clinical pregnancies, 122 babies (82 singletons and 40 twins) were registered. Among singletons, the rates of low birthweight (≤2500 g) and preterm birth (<37 weeks) were 6.1% and12%, respectively. Regarding malformation rate per live births, 4/122 (3.3%, 95% confidence interval: 0.9-8.2%) babies with ICD-10 malformations were recorded. This is the first report on neo-natal outcomes deriving from PF-ICSI. Although based on a limited cohort, results do not suggest an increase of adverse outcomes, including malformation rates, following this procedure.

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas.

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.

25-gauge pars plana vitrectomy with medium-term postoperative perfluoro-n-octane for the repair of giant retinal tears.

PURPOSE: The purpose of this study was to describe the treatment of giant retinal tears (GRTs) with 25-gauge pars plana vitrectomy (PPV) and medium-term postoperative perfluoro-n-octane (MT-PFO). METHODS: The study was a retrospective interventional case series of consecutive patients with GRTs treated with 25-gauge PPV and postoperative MT-PFO for a period of 2-3 weeks. A second, staged procedure was performed in all patients for PFO removal. RESULTS: Twenty-three eyes of 22 patients were studied, with a mean follow-up of 33.04 ± 19.74 months. Successful reattachment was achieved in 91.3 % of eyes (21/23) after MT-PFO. Retinal re-detachment occurred in five eyes, which was caused by proliferative vitreoretinopathy. Additional complications included cataract progression (n = 10), foreign body response (30.4 %, 7/23), and transient intraocular pressure (IOP) elevation (8/23, 34.8 %). Transient IOP elevation was associated with worse visual outcome (p = 0.01). CONCLUSIONS: MT-PFO was found to be an effective and safe technique for operative management of GRTs. In the majority of patients, retinas remained attached without further surgical intervention. Cataract progression, intraocular inflammation, and associated increased intraocular pressure are potential complications of MT-PFO.

The role of rhinovirus in children hospitalized for acute respiratory disease, Santa Fe, Argentina.

Human rhinoviruses (HRVs) were historically considered upper airway pathogens. However, they have recently been proven to cause infections in the lower respiratory tract, resulting in hospitalization of children with pneumonia, bronchiolitis, and chronic pulmonary obstruction. In this report, HRV frequency and seasonality are described together with patient clinical-epidemiological aspects. From a total of 452 surveyed samples, the HRV nucleic acids was detected in 172 (38.1%) and found in every month of the study year. 60% of inpatients with acute respiratory infection (ARI) associated with HRV were under 6 months of age and 31% had a clinical history, being preterm birth and recurrent wheezing the prevailing conditions. The most frequent discharge diagnoses were pneumonia (35.2%), bronchiolitis (32.4%), and bronchitis (12.4%). Fifteen point nine percent of patients required admission into intensive care units. The results obtained in this study demonstrated the association between HRV and children hospitalizations caused by ARI.

Outcomes of treatment of pediatric choroidal neovascularization with intravitreal antiangiogenic agents: the results of the KKESH International Collaborative Retina Study Group.

PURPOSE: To evaluate safety and clinical results of intravitreal antiangiogenic agents for choroidal neovascularization in pediatric patients. METHODS: Retrospective, multicenter, interventional case series. A total of 45 eyes of 39 pediatric patients with choroidal neovascularization of various etiologies were treated with intravitreal injection of antiangiogenic agents (1.25 mg per 0.05 mL of bevacizumab or 0.5 mg per 0.05 mL of ranibizumab). RESULTS: There were 24 girls and 15 boys with group median age of 13 years (range, 3-17 years). Mean follow-up period was 12.8 months (range, 3-60 months). Median visual acuity in terms of logarithm of the minimum angle of resolution at presentation and last follow-up was 0.87 and 0.7, respectively (P = 0.0003). Mean and median number of injections received over the follow-up period was 2.2 and 1, respectively. At the last follow-up, 22 eyes (48%) gained more than 3 lines of vision and 27 eyes (60%) had final visual acuity 20/50 or better. Nine eyes (20%) did not improve and had severe vision loss (20/200 or worse). CONCLUSION: Intravitreal antiangiogenic therapy for choroidal neovascularization in pediatric patients seems temporarily safe and effective in majority of affected eyes. Because of the rarity and character of this condition, it is unlikely that any clinical trials will soon take place to study this or other treatment option.

Moderate patient-prosthesis mismatch predicts cardiac events and advanced functional class in young and middle-aged patients undergoing surgery due to severe aortic stenosis.

BACKGROUND AND AIM: The clinical impact of patient-prosthesis mismatch (PPM) on outcomes in young and middle-aged patients undergoing surgery for aortic valve replacement (AVR) remains unknown. Our objective was to examine the mid-term impact of PPM on overall mortality, quality of life, and cardiac events in this population. METHODS: All patients younger than 70 years of age undergoing isolated AVR from October 2005 to October 2011 were analyzed. PPM was defined as the indexed effective orifice area ≤ 0.85 cm(2) /m(2) . We studied the impact of PPM on mid-term overall mortality, cardiac events, and New York Heart Association functional class using an analysis stratified for propensity score. Cardiac events were defined as cardiac death, sudden death, hospital readmission due to angina, syncope or heart failure or reoperation on aortic prosthesis. RESULTS: Two hundred and ninety-three patients were included in the study, of whom 81 (27.61%) had some degree of PPM. PPM had no impact on mid-term overall mortality (HR=1.45; 95% CI=0.65-3.22; p=0.36), although it had a negative impact on cardiac events (HR=11.52; 95% CI=5.25-25.24; p<0.001) and functional class (RR=7.55; 95% CI=2.59-22.03; p<0.001). CONCLUSIONS: Moderate PPM appears to be a strong and independent predictor of cardiac events and advanced functional class in young and middle-aged patients undergoing AVR for severe stenosis. However, it is possible that it has no impact on overall mortality.

Plasma levels of complement components C5 and C9 are associated with thrombin generation.

BACKGROUND: The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. OBJECTIVES: This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. METHODS: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Français du Sang Alpes-Méditerranée [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. RESULTS: Eighteen proteins were associated (P < 1.33 × 10⁻4) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. CONCLUSION: This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.