Vitamin E intake from natural sources and head and neck cancer risk : a pooled analysis in the International Head and Neck Cancer Epidemiology consortium.

BACKGROUND: Evidence for the possible effect of vitamin E on head and neck cancers (HNCs) is limited. METHODS: We used individual-level pooled data from 10 case-control studies (5959 cases and 12 248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium to assess the association between vitamin E intake from natural sources and cancer of the oral cavity/pharynx and larynx. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models applied to quintile categories of nonalcohol energy-adjusted vitamin E intake. RESULTS: Intake of vitamin E was inversely related to oral/pharyngeal cancer (OR for the fifth vs the first quintile category=0.59, 95% CI: 0.49-0.71; P for trend <0.001) and to laryngeal cancer (OR=0.67, 95% CI: 0.54-0.83, P for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral/pharyngeal cancer. Inverse associations were generally observed for the anatomical subsites of oral and pharyngeal cancer and within covariate strata for both sites. CONCLUSION: Our findings suggest that greater vitamin E intake from foods may lower HNC risk, although we were not able to explain the heterogeneity observed across studies or rule out certain sources of bias.

Molecular Analysis of NOTCH2 in Patients with Primary Open-Angle Glaucoma.

BACKGROUND AND PURPOSE: Transgenic mice overexpressing Notch2 in the uvea exhibit a hyperplastic ciliary body leading to increased IOP and glaucoma. The aim of this study was to investigate the possible presence of NOTCH2 variants in patients with primary open-angle glaucoma (POAG). METHODS: We screened DNA samples from 130 patients with POAG for NOTCH2 variants by denaturing high-performance liquid chromatography after PCR amplification and validated our data by direct Sanger sequencing. RESULTS: No mutations were observed in the coding regions of NOTCH2 or in the splice sites. 19 known SNPs (single nucleotide polymorphisms) were detected. An SNP located in intron 24, c.[4005+45A>G], was seen in 28.5% of the patients (37/130 patients). As this SNP is reported to have a minor allele frequency of 7% in the 1000 genomes database, it could be associated with POAG. However, we evaluated its frequency in an ethnic-matched control group of 96 subjects unaffected by POAG and observed a frequency of 29%, indicating that it was not related to POAG. CONCLUSION: NOTCH2 seemed to be a good candidate for POAG as it is expressed in the anterior segment in the human eye. However, mutational analysis did not show any causative mutation. This study also shows that proper ethnic-matched control groups are essential in association studies and that values given in databases are sometimes misleading.

Optimal Exchange Rate Policy in a Growing Semi-Open Economy

This paper considers an alternative perspective to China's exchange rate policy. It studies a semi-open economy where the private sector has no access to international capital markets but the central bank has full access. Moreover, it assumes limited financial development generating a large demand for saving instruments by the private sector. The paper analyzes the optimal exchange rate policy by modeling the central bank as a Ramsey planner. Its main result is that in a growth acceleration episode it is optimal to have an initial real depreciation of the currency combined with an accumulation of reserves, which is consistent with the Chinese experience. This depreciation is followed by an appreciation in the long run. The paper also shows that the optimal exchange rate path is close to the one that would result in an economy with full capital mobility and no central bank intervention.

La radiochirurgie dans le traitement de la douleur [Radiosurgery in Pain Treatment]

Le traitement de radiochirurgie par Gamma Knife (GK) est utilisé de plus en plus souvent comme une alternative à la microchirurgie conventionnelle pour le traitement des pathologies neurochirurgicales intracrâniennes. Il s'agit d'irradier en dose unique et à haute énergie, en condition stéréotaxique et à l'aide d'une imagerie multimodale (imagerie par résonance magnétique [IRM], tomodensitométrie et éventuellement artériographie). Le GK a été inventé par le neurochirurgien suédois Lars Leksell, qui a réalisé le premier ciblage du nerf trijumeau en 1951, sur la base d'une radiographie standard. Depuis, les progrès de l'informatique et de la robotique ont permis d'améliorer la technique de radiochirurgie qui s'effectue actuellement soit par accélérateur linéaire de particules monté sur un bras robotisé (Novalis®, Cyberknife®), soit par collimation de près de 192 sources fixes (GK). La principale indication radiochirurgicale dans le traitement de la douleur est la névralgie du nerf trijumeau. Les autres indications, plus rares, sont la névralgie du nerf glossopharyngien, l'algie vasculaire de la face, ainsi qu'un traitement de la douleur d'origine cancéreuse par hypophysiolyse. Gamma Knife surgery (GKS) is widely used as an alternative to open microsurgical procedures as noninvasive treatment of many intracranial conditions. It consists of delivering a single dose of high energy in stereotactic conditions, and with the help of a multimodal imaging (e.g., magnetic resonance imaging [MRI], computer tomography, and eventually angiography). The Gamma Knife (GK) was invented by the Swedish neurosurgeon Lars Leksell who was the first to treat a trigeminal neuralgia sufferer in 1951 using an orthogonal X-ray tube. Since then, the progresses made both in the field of informatics and robotics have allowed to improve the radiosurgical technique, which is currently performed either by a linear accelerator of particles mounted on a robotized arm (Novalis®, Cyberknife®), or by collimation of 192 fixed Co-60 sources (GK). The main indication of GKS in the treatment of pain is trigeminal neuralgia. The other indications, less frequent, are: glossopharyngeal neuralgia, cluster headache, and hypophysiolyse for cancer pain.

A thematic analysis of delusion with religious content in schizophrenia: open, closed, and mixed dynamics

The aim of the present study was to elicit how patients with delusions with religious contents conceptualized or experienced their spirituality and religiousness. Sixty-two patients with present or past religious delusions went through semistructured interviews, which were analyzed using the three coding steps described in the grounded theory. Three major themes were found in religious delusions: ''spiritual identity,'' ''meaning of illness,'' and ''spiritual figures.'' One higher-order concept was found: ''structure of beliefs.'' We identified dynamics that put these personal beliefs into a constant reconstruction through interaction with the world and others (i.e., open dynamics) and conversely structural dynamics that created a complete rupture with the surrounding world and others (i.e., closed structural dynamics); those dynamics may coexist. These analyses may help to identify psychological functions of delusions with religious content and, therefore, to better conceptualize interventions when dealing with it in psychotherapy.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Endovascular Versus Open Abdominal Aortic Aneurysm: Best Decision.

Since the first implantation of an endograft in 1991, endovascular aneurysm repair (EVAR) rapidly gained recognition. Historical trials showed lower early mortality rates but these results were not maintained beyond 4 years. Despite newer-generation devices, higher rates of reintervention are associated with EVAR during follow-up. Therefore, the best therapeutic decision relies on many parameters that the physician has to take in consideration. Patient's preferences and characteristics are important, especially age and life expectancy besides health status. Aneurysmal anatomical conditions remain probably the most predictive factor that should be carefully evaluated to offer the best treatment. Unfavorable anatomy has been observed to be associated with more complications especially endoleak, leading to more re-interventions and higher risk of late mortality. Nevertheless, technological advances have made surgeons move forward beyond the set barriers. Thus, more endografts are implanted outside the instructions for use despite excellent results after open repair especially in low-risk patients. When debating about AAA repair, some other crucial points should be analysed. It has been shown that strict surveillance is mandatory after EVAR to offer durable results and prevent late rupture. Such program is associated with additional costs and with increased risk of radiation. Moreover, a risk of loss of renal function exists when repetitive imaging and secondary procedures are required. The aim of this article is to review the data associated with abdominal aortic aneurysm and its treatment in order to establish selection criteria to decide between open or endovascular repair.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames.

Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.

Sources of variability of speech, spatial, and qualities of hearing scale (SSQ) scores in normal-hearing and hearing-impaired populations.

OBJECTIVE: To identify and quantify sources of variability in scores on the speech, spatial, and qualities of hearing scale (SSQ) and its short forms among normal-hearing and hearing-impaired subjects using a French-language version of the SSQ. DESIGN: Multi-regression analyses of SSQ scores were performed using age, gender, years of education, hearing loss, and hearing-loss asymmetry as predictors. Similar analyses were performed for each subscale (Speech, Spatial, and Qualities), for several SSQ short forms, and for differences in subscale scores. STUDY SAMPLE: One hundred normal-hearing subjects (NHS) and 230 hearing-impaired subjects (HIS). RESULTS: Hearing loss in the better ear and hearing-loss asymmetry were the two main predictors of scores on the overall SSQ, the three main subscales, and the SSQ short forms. The greatest difference between the NHS and HIS was observed for the Speech subscale, and the NHS showed scores well below the maximum of 10. An age effect was observed mostly on the Speech subscale items, and the number of years of education had a significant influence on several Spatial and Qualities subscale items. CONCLUSION: Strong similarities between SSQ scores obtained across different populations and languages, and between SSQ and short forms, underline their potential international use.