ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

A Braf kinase-inactive mutant induces lung adenocarcinoma.

The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.

Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.

Expression analysis and tissue localization of IgZ in the grouper Epinephelus coioides after Vibrio alginolyticus infection and vaccination.

The orange-spotted grouper (Epinephelus coioides) is an important marine farmed fish in China. It is affected by the bacterial pathogen Vibrio alginolyticus, which causes high mortality and substantial economic losses. We studied the transcriptional changes of the IgZ gene in E. coioides following V. alginolyticus stimulation and investigated the distribution of IgZ in different tissues. The highest expression level of IgZ occurred in the head kidney. When fish were stimulated with live and inactivated V. alginolyticus, the expression levels of IgZ in the head kidney, spleen, intestine, gills and blood cells were significantly upregulated. In an in situ hybridization study, IgZ mRNA-positive cells were detected in the head kidney, spleen and gill, but positive signals were not detected in the liver and intestine. IgZ-labelled cells increased in the head kidney, spleen and gills post-infection with V. alginolyticus for 21 days. The present study provides additional evidence that IgZ is involved in mucosal immune responses and helps explain the role of IgZ in E. coioides defence against V. alginolyticus infection.

Fractionation in adjuvant radiotherapy for invasive breast cancer and ductal carcinoma in situ in Ontario, Canada from 2009 to 2015.

The use of hypofractionated radiotherapy (HFRT) in patients with breast cancer and ductal carcinoma in situ (DCIS) in Ontario, Canada, from 2009 to 2015 was reported. A retrospective cohort study was conducted using data from the Institute for Clinical Evaluative Sciences (ICES). Patients with a breast cancer or DCIS diagnosis between 2009 and 2015 who received adjuvant breast or chest wall radiation were included. Trends in HFRT use (≤16 fractions) and factors associated with HFRT use in a multivariable logistic regression model with physician-level random effect were reported. The approximate number of hours that could be saved if all patients were to receive HFRT was calculated. A total of 42 072 patients were included. All included characteristics were significantly associated with HFRT use. Hypofractionated radiotherapy use in patients with breast cancer and DCIS increased to around 75% in 2015. In stage I/II patients with mastectomy and chest wall radiation, HFRT use increased to 40% in 2015. Hypofractionated radiotherapy use in patients with regional nodal radiation or reconstruction has increased but remains under 20%. For breast cancer patients with breast-conserving surgery (BCS) and breast radiation, 56 265 visits corresponding to 7200 hours of treatment or 3500 additional HFRT courses could have been saved. In conclusion, HFRT use in Ontario has increased in all patient populations but is nonuniform among physicians and institutions. Use of HFRT in chest wall and regional nodal radiation remains relatively lower than in breast cancer and DCIS patients with BCS.

Identification of Leaf Rust Resistance Genes in Bread Wheat Cultivars from Ethiopia.

Wheat leaf rust, caused by Puccinia triticina (Pt), is a widespread disease of bread wheat worldwide. In the present study, 50 wheat cultivars from Ethiopia and 34 differential lines, mostly near-isogenic lines (NILs) in the background of Thatcher with known resistance genes to leaf rust (Lr), were tested with 14 Pt races in the greenhouse to postulate Lr genes at the seedling stage. Field experiments were also conducted to identify adult plant responses to leaf rust in Baoding in the 2017-2018 and 2018-2019 growing seasons and in Zhoukou in the 2018-2019 growing season. Thirteen Lr genes (Lr1, Lr18, Lr3ka, Lr15, Lr26, Lr20, Lr14a, Lr30, Lr2a, Lr11, Lr34, Lr46, and Lr68) either singly or in combination were found in 39 cultivars. Known Lr genes were not present in the remaining 11 cultivars. Lr1 and Lr46, each in 13 cultivars, and Lr34 in 12 cultivars were the most commonly identified resistance genes. Less frequently identified genes included Lr26 (five cultivars); Lr30 and Lr18 (each present in four cultivars); Lr15, Lr3ka, and Lr2a (each identified in three cultivars); and Lr68 (two cultivars). Evidence for the existence of Lr11, Lr20, and Lr14a (each in one cultivar) was also obtained. Twenty-one cultivars were found to have slow rusting resistance to leaf rust in the field tests. The results should be valuable for cultivar selection with combinations of effective Lr genes and used in breeding new cultivars with improved resistance to leaf rust in Ethiopia and China.

The risk of death within 5 years of first hospital admission in older adults.

BACKGROUND: The risk of death in people after their first admission to hospital or first presentation to the emergency department for any reason is not known. The objective of this study was to estimate the risk of death among older adults who had had no admissions to hospital or emergency department visits in the preceding 5 years. METHODS: We used administrative data from Ontario, Canada, from 2007 to 2017 to measure the 5-year risk of death in community-dwelling adults aged 66 years and older after their first planned or unplanned hospital admission or emergency department visit, and among those who were neither admitted to hospital nor presented to the emergency department. We describe how this risk varied by age. RESULTS: Among 922 074 community-dwelling older adults, 12.7% died (116 940 deaths) over a follow-up of 3 112 528 person-years (standardized mortality rate 53.8 per 1000 person-years). After the first unplanned hospital admission, 39.7% died (59 234 deaths, standardized mortality rate 127.6 per 1000 person-years). After the first planned hospital admission, 13.0% died (10 775 deaths, standardized mortality rate 44.6 per 1000 person-years). After the first visit to the emergency department, 10.9% died (35 663 deaths, standardized mortality rate 36.2 per 1000 person-years). Among those with neither an emergency department visit nor hospital admission during follow-up, 3.1% died (11 268 deaths, standardized mortality rate 29.6 per 1000 person-years). Slightly more than half of all deaths were in those with first unplanned hospital admission (50.7%). INTERPRETATION: Death within 5 years of first unplanned hospital admission for older adults is frequent and common. Knowledge of this risk may influence counselling and patient preferences and may be useful in research and analyses for health system planning.

Predicting High Health Care Resource Utilization in a Single-payer Public Health Care System: Development and Validation of the High Resource User Population Risk Tool.

BACKGROUND: A large proportion of health care spending is incurred by a small proportion of the population. Population-based health planning tools that consider both the clinical and upstream determinants of high resource users (HRU) of the health system are lacking. OBJECTIVE: To develop and validate the High Resource User Population Risk Tool (HRUPoRT), a predictive model of adults that will become the top 5% of health care users over a 5-year period, based on self-reported clinical, sociodemographic, and health behavioral predictors in population survey data. RESEARCH DESIGN: The HRUPoRT model was developed in a prospective cohort design using the combined 2005 and 2007/2008 Canadian Community Health Surveys (CCHS) (N=58,617), and validated using the external 2009/2010 CCHS cohort (N=28,721). Health care utilization for each of the 5 years following CCHS interview date were determined by applying a person-centered costing algorithm to the linked health administrative databases. Discrimination and calibration of the model were assessed using c-statistic and Hosmer-Lemeshow (HL) χ statistic. RESULTS: The best prediction model for 5-year transition to HRU status included 12 predictors and had good discrimination (c-statistic=0.8213) and calibration (HL χ=18.71) in the development cohort. The model performed similarly in the validation cohort (c-statistic=0.8171; HL χ=19.95). The strongest predictors in the HRUPoRT model were age, perceived general health, and body mass index. CONCLUSIONS: HRUPoRT can accurately project the proportion of individuals in the population that will become a HRU over 5 years. HRUPoRT can be applied to inform health resource planning and prevention strategies at the community level.

Temporal Trends in Mental Health Service Utilization across Outpatient and Acute Care Sectors: A Population-Based Study from 2006 to 2014.

OBJECTIVE: Although evidence suggests that treatment seeking for mental illness has increased over time, little is known about how the health system is meeting the increasing demand for services. We examined trends in physician-based mental health service use across multiple sectors. METHOD: In this population-based study, we used linked health-administrative databases to measure annual rates of mental health-related outpatient physician visits to family physicians and psychiatrists, emergency department visits, and hospitalizations in adults aged 16+ from 2006 to 2014. We examined absolute and relative changes in visit rates, number of patients, and frequency of visits per patient, and assessed temporal trends using linear regressions. RESULTS: Among approximately 11 million Ontario adults, age- and sex-standardized rates of mental health-related outpatient physician visits declined from 604.8 to 565.5 per 1000 population over the study period ( Ptrend = 0.04). Over time, the rate of visits to family physicians/general practitioners remained stable ( Ptrend = 0.12); the number of individuals served decreased, but the number of visits per patient increased. The rate of visits to psychiatrists declined ( Ptrend < 0.001); the number of individuals served increased, but the number of visits per patient decreased. Concurrently, visit rates to emergency departments and hospitals increased (16.1 to 19.7, Ptrend < 0.001 and 5.6 to 6.0, Ptrend = 0.01, per 1000 population, respectively). Increases in acute care service use were greatest for anxiety and addictions. CONCLUSIONS: The increasing acute care service use coupled with the reduction in outpatient visits suggest, overall, an increase in demand for mental health care that is not being met in ambulatory care settings.

A population-based study of the risk of osteoporosis and fracture with dutasteride and finasteride.

BACKGROUND: Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. METHODS: We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. RESULTS: We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). CONCLUSIONS: Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.

Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.

BACKGROUND: Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness. METHODS: We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins. RESULTS: Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82). INTERPRETATION: In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients.

The appropriateness and persistence of testosterone replacement therapy in Ontario.

PURPOSE: To examine the concordance between testosterone replacement therapy (TRT) use and established reimbursement criteria, as well as compare the persistence of use among available formulations (injectable, oral, topical gel, transdermal patch) among elderly men in Ontario, Canada. METHODS: We conducted a retrospective cohort study of men aged 66 years or older in Ontario newly treated with testosterone between 1 January 2009 and 31 December 2012 using linked health administrative data. Continuous use was defined on the basis of prescription refills issued within 180 days of the preceding prescription. We studied men who received at least two consecutive TRT prescriptions. We estimated the prevalence of hypogonadism, human immunodeficiency virus, specialist visits and lab tests for serum testosterone prior to initiation of TRT to investigate concordance with prescribing criteria. We also performed a Kaplan-Meier analysis to test for differences in the median time to discontinuation among formulations. RESULTS: Among the 4797 men who received at least two TRT prescriptions, only 38.7% met the reimbursement criteria for use prior to initiating therapy. The median time to discontinuation differed significantly among formulations and was longest among recipients of oral TRT products (383 days), and lower for recipients of topical gels (319 days), injectable (283 days) and transdermal patches (160 days; Log-rank test p < 0.001). CONCLUSIONS: A large proportion of older men in Ontario do not appear to meet reimbursement criteria prior to commencing therapy, and many discontinue TRT within a year of initiation. Copyright © 2016 John Wiley & Sons, Ltd.

p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.

Identification of Leaf Rust Resistance Genes in Chinese Common Wheat Cultivars.

Puccinia triticina Eriks. (Pt), the causal agent of wheat (Triticum aestivum L.) leaf rust, is the most widespread disease of common wheat worldwide. In the present study, 83 wheat cultivars from three provinces of China and 36 tester lines with known leaf rust resistance (Lr) genes were inoculated in the greenhouse with 18 Pt pathotypes to identify seedling effective Lr genes. Field tests were also performed to characterize slow leaf rusting responses at the adult plant growth stage in Baoding and Zhoukou in the 2014-15 and 2015-16 cropping seasons. Twelve Lr genes, viz. Lr1, Lr26, Lr3ka, Lr11, Lr10, Lr2b, Lr13, Lr21, Lr34, Lr37, Lr44, and Lr46 either singly or in combination were identified in 41 cultivars. Known Lr genes were not detected in the remaining 42 cultivars. The most commonly identified resistance genes were Lr26 (20 cultivars), Lr46 (18 cultivars), and Lr1 (eight cultivars). Less frequently detected genes included Lr13, Lr34, and Lr37 (each present in four cultivars), Lr10 (three cultivars), and Lr3ka and Lr44 (each in two cultivars). Evidence for the presence of genes Lr11, Lr2b, and Lr21 (each in one cultivar) was also obtained. Seventeen cultivars were found to have slow rusting resistance in both field growing seasons.

Socioeconomic status and risk of hemorrhage during warfarin therapy for atrial fibrillation: A population-based study.

BACKGROUND: Among patients taking warfarin, lower socioeconomic status is associated with poorer control of anticoagulation. However, the extent to which socioeconomic status influences the risk of hemorrhage is unknown. We examined the extent to which socioeconomic status influences the risk of hemorrhage in older individuals newly commencing warfarin therapy for atrial fibrillation. METHODS: We conducted a population-based cohort study of individuals 66 years or older with atrial fibrillation who commenced warfarin therapy between April 1, 1997, and November 30th 2011, in Ontario, Canada. We used neighborhood-level income quintiles as a measure of socioeconomic status. The primary outcome was an emergency department visit or hospitalization for hemorrhage, and the secondary outcome was fatal hemorrhage. RESULTS: We studied 166,742 older patients with atrial fibrillation who commenced warfarin therapy. Of these, 16,371 (9.8%) were hospitalized for hemorrhage during a median follow-up of 369 (interquartile range 102-865) days. After multivariable adjustment using Cox proportional hazards regression, we found that those in the lowest-income quintile faced an increased risk of hospitalization for hemorrhage relative to those in the highest quintile (adjusted hazard ratio 1.18, 95% CI 1.12-1.23). Similarly, the risk of fatal hemorrhage (n = 1,802) was increased in the lowest-income relative to the highest-income quintile (adjusted hazard ratio 1.28, 95% CI 1.11-1.48). CONCLUSIONS: Among older individuals receiving warfarin therapy for atrial fibrillation, lower socioeconomic status is a risk factor for hemorrhage and hemorrhage-related mortality. This factor should be carefully considered when initiating and monitoring warfarin therapy.

Public Drug Coverage and Its Impact on Triptan Use Across Canada: A Population-Based Study.

BACKGROUND: Public drug coverage for triptan medications varies across jurisdictions in Canada, which may lead to differences in usage patterns and patient risk for medication overuse headache. METHODS: We conducted a population-based, cross-sectional analysis of publicly funded triptan use in seven provinces across Canada from January 1, 2012 to December 31, 2012. All patients who had filled at least one prescription for a triptan during the study period were included. We defined quantity limits of 6, 12, and 18 triptan units per month to assess the prevalence of high volumes of triptan use, which may place patients at risk for medication overuse headaches, and compared this prevalence between provinces with different funding restrictions. RESULTS: We identified 14,085 publicly funded users of triptans in 2012 in the seven provinces studied, 82.5% of whom were aged less than 65 years (N = 11,631). The prevalence of triptan use ranged substantially by province, from 0.04% in Ontario to a maximum of 1.0% in Manitoba (P < .001). Furthermore, the percentage of patients in each province using more than 6, 12, or 18 units per month differed significantly between provinces (P < .001). In particular, the percentage of patients treated with more than 6 units per month ranged from as low as 2.1% in Saskatchewan to 43.8% in Ontario. CONCLUSIONS: Differing public drug reimbursement criteria for triptans may be one contributing factor that has led to our observation of considerable variation in both prevalence of triptan prescribing and potential overuse of these medications. We offer that monthly quantity limits may be considered as a tool to decrease risks for medication overuse headache.

Safety of valproic acid in patients with chronic obstructive pulmonary disease: a population-based cohort study.

PURPOSE: Valproic acid is an anticonvulsant that also inhibits histone deacetylase (HDAC), a property that could worsen pulmonary function in patients with chronic obstructive pulmonary disease (COPD). The clinical significance of this property is unknown. We therefore compared the risk of COPD exacerbation in older patients with COPD commencing treatment with either valproic acid or phenytoin, an anticonvulsant that does not affect HDAC. METHODS: We conducted a population-based retrospective cohort study of Ontario residents with COPD aged 66 years or older who started treatment with valproic acid or phenytoin between 1 April 1993 and 30 November 2012. The primary outcome was a hospital admission or emergency department visit for a COPD exacerbation within 240 days of drug initiation. A secondary outcome examined initiation of oral corticosteroids in the outpatient setting. RESULTS: During the study period, we identified 4596 COPD patients who commenced valproic acid and 8478 who commenced phenytoin. Following multivariable adjustment, valproic acid did not increase the risk of the primary outcome (adjusted hazard ratio 1.00, 95% confidence interval 0.79 to 1.26). Although valproic acid was associated with a lower risk of initiating oral corticosteroids in the first thirty days following commencement of anticonvulsant therapy (adjusted hazard ratio 0.32; 95% confidence interval 0.21 to 0.49), no difference was observed during subsequent follow-up. CONCLUSION: Among older patients with COPD, treatment with valproic acid does not increase the risk of adverse pulmonary outcomes relative to phenytoin. These findings suggest that valproate-induced HDAC inhibition is of little clinical relevance in this context.

Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study.

BACKGROUND: Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for the treatment of hypertension. OBJECTIVE: To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide in older adults. DESIGN: Propensity score-matched observational cohort study with up to 5 years of follow-up. SETTING: Ontario, Canada. PATIENTS: All individuals aged 66 years or older who were newly treated with chlorthalidone or hydrochlorothiazide and were not hospitalized for heart failure, stroke, or myocardial infarction in the prior year were eligible for inclusion. Each chlorthalidone recipient was matched to up to 2 hydrochlorothiazide recipients on the basis of age, sex, year of treatment initiation, and propensity score. MEASUREMENTS: The primary outcome was a composite of death or hospitalization for heart failure, stroke, or myocardial infarction. Safety outcomes included hospitalization with hypokalemia or hyponatremia. RESULTS: A total of 29 873 patients were studied. During follow-up, chlorthalidone recipients (n = 10 384) experienced the primary outcome at a rate of 3.2 events per 100 person-years of follow-up, and hydrochlorothiazide recipients experienced 3.4 events per 100 person-years of follow-up (adjusted hazard ratio, 0.93 [95% CI, 0.81 to 1.06]). Patients treated with chlorthalidone were more likely to be hospitalized with hypokalemia (adjusted hazard ratio, 3.06 [CI, 2.04 to 4.58]) or hyponatremia (adjusted hazard ratio, 1.68 [CI, 1.24 to 2.28]). In 9 post hoc analyses comparing patients initially prescribed 12.5, 25, or 50 mg of chlorthalidone per day with those prescribed 12.5, 25, or 50 mg of hydrochlorothiazide per day, the former were more likely to be hospitalized with hypokalemia for all 6 comparisons in which a statistically significant association was found. The results of other effectiveness and safety outcomes were also consistent with those of the main analysis. LIMITATION: Unmeasured differences in baseline characteristics or physician treatment approaches or an insufficiently large sample may have limited the ability to detect small differences in the comparative effectiveness of the drugs. CONCLUSION: As typically prescribed, chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia. PRIMARY FUNDING SOURCE: Ontario Ministry of Health and Long-Term Care.

Self-calibrated atom-interferometer gyroscope by modulating atomic velocities.

Atom-interferometer gyroscopes have attracted much attention for their long-term stability and extremely low drift. For such high-precision instruments, self-calibration to achieve an absolute rotation measurement is critical. In this work, we propose and demonstrate the self-calibration of an atom-interferometer gyroscope. This calibration is realized by using the detuning of the laser frequency to control the atomic velocity, thus modulating the scale factor of the gyroscope. The modulation determines the order and the initial phase of the interference stripe, thus eliminating the ambiguity caused by the periodicity of the interferometric signal. This self-calibration method is validated through a measurement of the Earth's rotation rate, and a relative uncertainty of 162 ppm is achieved. Long-term stable and self-calibrated atom-interferometer gyroscopes have important applications in the fields of fundamental physics, geophysics, and long-time navigation.