Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.

The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.

Effects of genetic selection on activity of corticotropic and thyrotropic axes in modern broiler chickens.

Commercial selection for meat-type (broiler) chickens has produced economically valuable birds with fast growth rates, enhanced muscle mass, and highly efficient feed utilization. The physiological changes that account for this improvement and unintended consequences associated with them remain largely unexplored, despite their potential to guide further advancements in broiler production efficiency. To identify effects of genetic selection on hormonal signaling in the adrenocorticotropic and thyrotropic axes, gene expression in muscle and liver and post-hatch circulating hormone concentrations were measured in legacy [Athens Canadian Random Bred (ACRB)] and modern (Ross 308) male broilers between embryonic days (e) 10 and e18 and post-hatch days (d) 10 and d40. No interactive effects or main effects of line were observed for adrenocorticotropic gene expression during either developmental period, although age effects appeared for corticosteroid-binding globulin in liver during embryogenesis and post-hatch and glucocorticoid receptor in both tissues post-hatch. There was a main line effect for circulating corticosterone, with levels in ACRB greater than those in Ross. Several thyrotropic genes exhibited line-by-age interactions during embryonic or post-hatch development. In liver, embryonic expression of thyroid hormone receptor beta was greater in ACRB on e12, and deiodinase 3 (DIO3) levels were greater in Ross on e14 and e16. In juvenile liver, deiodinase 2 (DIO2) expression was greater in ACRB on d10 but greater in Ross on d20, while DIO3 was higher in ACRB on d30 and d40. Levels of thyroid hormone receptor alpha mRNA exhibited a main line effect, with levels greater in ACRB juvenile breast muscle. Several thyrotropic genes exhibited main age effects, including DIO2 and DIO3 in embryonic breast muscle, thyroid hormone receptor alpha and thyroid hormone receptor beta in post-hatch liver, and DIO2 in post-hatch breast muscle. Circulating triiodothyronine displayed a main line effect, with levels in Ross significantly reduced as compared to ACRB. These findings suggest that in modern broilers, a decrease in levels of hormones that control basal metabolism triiodothyronine and the stress response circulating corticosterone, as well as altered expression of genes regulating thyroid hormone activity, could contribute to lower heat production, reduced stress response, and altered nutrient partitioning, leading to more efficient feed utilization and faster, more productive growth.

Estimating survival in advanced cancer: a comparison of estimates made by oncologists and patients.

PURPOSE: To compare estimates of expected survival time (EST) made by patients with advanced cancer and their oncologists. METHODS: At enrolment patients recorded their "understanding of how long you may have to live" in best-case, most-likely, and worst-case scenarios. Oncologists estimated survival time for each of their patients as the "median survival of a group of identical patients". We hypothesized that oncologists' estimates of EST would be unbiased (~ 50% longer or shorter than the observed survival time [OST]), imprecise (< 33% within 0.67 to 1.33 times OST), associated with OST, and more accurate than patients' estimates of their own survival. RESULTS: Twenty-six oncologists estimated EST for 179 patients. The median estimate of EST was 6.0 months, and the median OST was 6.2 months. Oncologists' estimates were unbiased (56% longer than OST), imprecise (27% within 0.67 to 1.33 times OST), and significantly associated with OST (HR 0.88, 95% CI 0.82 to 0.93, p < 0.01). Only 41 patients (23%) provided a numerical estimate of their survival with 107 patients (60%) responding "I don't know". The median estimate by patients for their most-likely scenario was 12 months. Patient estimates of their most-likely scenario were less precise (17% within 0.67 to 1.33 times OST) and more likely to overestimate survival (85% longer than OST) than oncologist estimates. CONCLUSION: Oncologists' estimates were unbiased and significantly associated with survival. Most patients with advanced cancer did not know their EST or overestimated their survival time compared to their oncologist, highlighting the need for improved prognosis communication training. Trial registration ACTRN1261300128871.

Luminescence from nearly isolated surface defects in silica nanoparticles.

A structured emission/excitation pattern, proper of isolated defects, arises in a vacuum from silica nanoparticles. The luminescence, centered around 3.0-3.5 eV, is characterised by a vibronic progression due to the phonon coupling with two localised modes of frequency ∼1370 cm(-1) and ∼360 cm(-1), and decays in about 300 ns at 10 K. On increasing the temperature, the intensity and the lifetime decrease due to the activation of a non-radiative rate from the excited state. Concurrently, the temperature dependence of the lineshape evidences the low coupling with non-localised modes of the matrix (Huang-Rhys factor S ~ 0.2) and the poor influence of the inhomogeneous broadening. These findings outline an uncommon behaviour in the field of the optical properties of defects in amorphous solids, evidencing that the silica surface can allocate luminescent defects almost disentangled from the basal network.

Immigrants' perceptions of the quality of their cancer care: an Australian comparative study, identifying potentially modifiable factors.

BACKGROUND: Recent data show a falling cancer mortality in the general population without a similar shift in immigrant outcomes, leading to a greater cancer burden and mortality for immigrants. Our aims were to compare perceived patterns of care in immigrants and native-born cancer patients. PATIENTS AND METHODS: This was a hospital-based sample of first-generation immigrants and Australian-born Anglo patients in the first year following diagnosis. It was restricted to Chinese, Arabic, or Greek speakers. Eligible participants, recruited via 16 oncology clinics, were over 18, with cancer (any type or stage), and having commenced treatment at least 1 month previously. Five hundred and seventy-one CALD patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. RESULTS: Immigrants had difficulty communicating with the doctor (73% versus 29%) and understanding the health system (38% versus 10%). Differences were found in 'difficulty knowing who to see' (P = 0.0002), 'length of time to confirm diagnosis' (P = 0.04), wanting more choice about a specialist and hospital (P < 0.0001); being offered the opportunity to see a counselor (P < 0.0001); and actually seeing one (P < 0.0001). There were no significant self-reported differences regarding how cancer was detected, time to see a health professional, or type first seen; however, immigrants reported difficulty knowing who to see. Previous studies showed differences in patterns of care according to socioeconomic status (SES) and educational level. Despite adjusting for age, sex, education, marital status, SES, time since diagnosis, and type of cancer, we did not find significant differences. Instead, we found that understanding of the health system and confidence understanding English were important factors. CONCLUSIONS: This study confirmed that immigrants with cancer perceive an inferior quality of cancer care. We highlight potentially modifiable factors including assistance in navigating the health system, translated information, and cultural competency training for health professionals.

The structural disorder of a silica network probed by site selective luminescence of the nonbridging oxygen hole centre.

We studied the inhomogeneous distribution of the luminescence band associated with the nonbridging oxygen hole centre in silica through site selective excitation/detection of the zero phonon line by a tunable laser source. Defects induced in the bulk of synthetic samples by γ and ß exposure exhibit an increase of the inhomogeneous width from 0.071 to 0.086 eV on increasing the irradiation dose from 2 × 10(6) to 5 × 10(9) Gy. We also investigated two defect variants stabilized at the surface of the silica nanoparticles, (≡ Si-O)3 Si­O* and (≡ Si-O)2(H-O)Si-O*, whose inhomogeneous width was measured to be 0.042 eV and 0.060 eV, respectively. These results can be accounted for by the structural disorder around the defect, and specific causes of its variation can be pointed out, such as the network modification induced by irradiation or the structural alteration near the SiO(4) coordination sphere.

Selective coupling of HE11 and TM01 modes into microfabricated fully metal-coated quartz probes.

We report computational and experimental investigations on injection and transmission of light in microfabricated fully Aluminum-coated quartz probes. In particular, we show that a selective coupling of either the HE(11) or the TM(01) mode can be carried out by injecting focused linearly or radially polarized beams into the probe. Optical fields, emitted by the probe after a controlled injection, are characterized in intensity and phase with the help of an interferometric technique. With the help of near-field measurement, we finally demonstrate that a longitudinally polarized spot localized at the tip apex is actually produced when the TM(01) mode is coupled into the probe.

Observation of amplitude and phase in ridge and photonic crystal waveguides operating at 1.55 microm by use of heterodyne scanning near-field optical microscopy.

We apply heterodyne scanning near-field optical microscopy (SNOM) to observe with subwavelength resolution the amplitude and phase of optical fields propagating in several microfabricated waveguide devices operating around the 1.55 microm wavelength. Good agreement between the SNOM measurements and predicted optical mode propagation characteristics in standard ridge waveguides demonstrates the validity of the method. In situ observation of the subwavelength-scale distribution and propagation of optical fields in straight and 90 degrees bend photonic crystal waveguides facilitates a more detailed understanding of the optical performance characteristics of these devices and illustrates the usefulness of the technique for investigating nanostructured photonic devices.

Efficient O-trimethylsilylation of alcohols and phenols with trimethylsilyl azide catalyzed by tetrabutylammonium bromide under neat conditions.

A very efficient procedure for the trimethylsilylation of a wide variety of alcohols, including primary, allylic, benzylic, secondary, hindered secondary, tertiary, and phenols is reported. The reactions were carried out under neat conditions with trimethylsilyl azide (TMSN(3)) and, when necessary, in the presence of a catalytic amount (20 mol %) of tetrabutylammonium bromide (TBABr) at 30 or 70 degrees C. Under catalytic conditions, the yields of the corresponding trimethylsilyl ethers were greater than 91%. This procedure also allows the selective protection of primary and secondary alcohols in the presence of tertiary ones.

Bromolysis and iodolysis of alpha,beta-epoxycarboxylic acids in water catalyzed by indium halides.

The ring opening of alpha,beta-epoxycarboxylic acids by bromide and iodide ions has been efficiently carried out in water in high regio- and stereoselective fashion. The iodolysis of trans-beta-monoalkylated epoxycarboxylic acids at pH 4.0 was completely alpha-regioselective and anti diastereoselective. The InCl(3)-catalyzed iodolysis of a variety of alpha,beta-epoxycarboxylic acids at pH 1.5 gave the corresponding anti beta-iodohydrins in 88-95% yields. The one-pot synthesis of the alpha- and beta-hydroxyhexanoic acids, starting from the corresponding alpha,beta-epoxycarboxylic acid 1a by iodolysis followed by reduction of the resulting iodohydrins 4a and 4b by NaBH(4)-InCl(3) in water, has been performed.

Lewis-acid catalyzed organic reactions in water. The case of AlCl(3), TiCl(4), and SnCl(4) believed to be unusable in aqueous medium.

Classical Lewis acids such as AlCl(3), TiCl(4), and SnCl(4), believed to be unusable as catalysts in aqueous medium, efficiently catalyzed regio- and stereoselective azidolysis and iodolysis of alpha,beta-epoxycarboxylic acids in water at pH 4.0 and 1.5, respectively. The concept of water-tolerant metal-salt is reexamined in direct relationship to the aqua ion hydrolysis constant.

Azidolysis of alpha,beta-epoxycarboxylic acids. A water-promoted process efficiently catalyzed by indium trichloride at pH 4.0.

The catalytic efficiency of InCl(3), Yb(OTf)(3), and Sc(OTf)(3) in the azidolysis of alpha,beta-epoxycarboxylic acids has been studied in water and in organic solvents, for comparison using NaN(3) and Me(3)SiN(3) as the source of the azido group. In water, the catalytic effectiveness of these metal salts strongly depends on the pH of the aqueous medium and on the type of Lewis acid catalyst. In water their catalytic activity is mostly due to the corresponding aqua ion species, the concentration of which becomes significant when the pH of the aqueous medium is below the corresponding pK(1,1) hydrolysis constant. The process is more efficient in water than in organic solvents. At pH 4.0, InCl(3) is a far better catalyst than Yb(OTf)(3) or Sc(OTf)(3) and allows the highly regio- and diasteroselective preparation of beta-azido-alpha-hydroxycarboxylic acids, which can be isolated in pure form in very high yields.

Control of the vibration damping through surface functionalization of a shear force probe.

Shear force mapping on thiolipid Langmuir-Blodgett monolayers probed with Al-coated tips leads to a contrast highly dependent on the monolayer molecular organization, which does not correspond to the topographical relief of the sample. The use of functionalized surface probes offers the possibility to better control the probe-to-sample interaction. In addition, hydrophilic surface probes are totally insensitive to alkyl chain arrangements in the monolayer. Hydrophobic probes, instead, can be chosen to map shear force on soft samples in liquid environment, since their mechanical properties are not influenced by the surrounding liquid.

Is computed tomography of nonvisualized C7-T1 cost-effective?

The authors determined the cost-effectiveness of computed tomography (CT) of the inadequately visualized C7-T1 level on conventional radiography in a retrospective cohort study. Routine cervical spine radiography was performed in 360 trauma patients in whom the C7-T1 level was not adequately visualized, but there was no evidence of lower cervical spine injury. In these patients, CT of C7-T1 was performed and reviewed for the presence, location, and pattern of fracture. An orthopaedic surgeon was consulted regarding his proposed treatment and the presumed natural history without treatment of each C7-T1 injury identified. Based on Medicare reimbursement data, cost-effectiveness was then calculated for 1) each fracture identified, 2) each fracture that required surgical fixation secondary to risk of further neurologic sequelae (definitely unstable), and 3) each fracture that required either surgical fixation or halo immobilization secondary to the risk of development of cervical instability and arthritis (potentially or definitely unstable). Eleven of 360 fractures of C7-T1 were identified. The cost-effectiveness of CT for averting potential sequelae was $9,192 for each fracture identified, $16,852 identified for each potentially or definitely unstable fracture identified, and $50,557 for each definitely unstable fracture identified. Computed tomography of the inadequately visualized C7-T1 level on plain radiography is cost-effective, especially given the relatively young age of the trauma population and therefore the high associated morbidity of the sequelae of these injuries over time.

Evaluation of the efficacy of pidotimod in the exacerbations in patients affected with chronic bronchitis.

The efficacy and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new oral synthetic immunostimulating agent, were investigated in a multicentre study, performed in 10 university and hospital centres of pneumophthisiology and respiratory physiopathology, according to a double-blind vs. placebo experimental design. Primary objective of the investigation was to verify the efficacy of pidotimod against infectious exacerbations in patients affected with chronic bronchitis. 181 inpatients or outpatients (117 male, 64 female; mean age: 62.5 years), affected with chronic bronchitis, were enrolled in the study. Pidotimod 800 mg/die or placebo sachets were administered by oral route for 60 consecutive days, followed by a 60-day follow-up period. Clinical observations were performed at baseline (D 0), after 30 (D 30) and 60 (D 60) days of treatment, as well as at the end of the follow-up (D 120). Time and frequency of infectious relapses were considered as the target variable for the evaluation of the efficacy of the drug. Clinical picture, expectoration characteristics, spirometric parameters and laboratory tests were monitored to evaluate patients' conditions. The results indicate that pidotimod is significantly more effective than placebo against infectious relapses in patients suffering from chronic bronchitis. During the first month, 9% of patients treated with pidotimod were affected with an infectious relapse vs. 39.5% of patients treated with placebo (chi 2, p < 0.001). In the second month, infectious episodes were reported by 1.2% of patients treated with the drug vs. 46.1% of patients treated with placebo (chi 2, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Infarto en el territorio de la arteria coroidea anterior por accidente quirúrgico / Incidental surgical infarct in the territory of the anterior choroidal artery

Se comunican 2 casos de infarto en el territorio de la Arteria Coroidea Anterior. Ambas pacientes, mujeres de 19 y 47 años, fueron admitidas por clínica y tomografía computada (TC) de hemorragia subaracnoidea. En el postquirúrgico inmediato, de ectasia pediculada carotídea, vimos: desviación de cabeza y ojos a derecha,disartria,negligencia, así como hemiparesia con disestesias a izquierda. La angiografía (AG) verificadora de vasos de cuello y cerebro, mostró la correcta aplicación del clip en el cuello de sendos aneurismas. Ambas completaron la recuperación clínica antes del séptimo día y meses más tarde padecieron la primera crisis parcial compleja. Se observaron imágenes hipodensas temporales profundas y posteriores en TC. Nuestras pacientes continúan asintomáticas con carbamazepina. De 80 casos reportados, 38 fueron por cirugía adrede, ninguno casual y el resto ictales. Nuestros casos serían los únicos impensados. Consideramos que estos infartos tienen la suficiente categoría como para conformar una entidad clínica independiente