Competition between Allowed and First-Forbidden ß Decay: The Case of

The ß decay of ^{208}Hg into the one-proton hole, one neutron-particle _{81}^{208}Tl_{127} nucleus was investigated at CERN-ISOLDE. Shell-model calculations describe well the level scheme deduced, validating the proton-neutron interactions used, with implications for the whole of the N>126, Z<82 quadrant of neutron-rich nuclei. While both negative and positive parity states with spin 0 and 1 are expected within the Q_{ß} window, only three negative parity states are populated directly in the ß decay. The data provide a unique test of the competition between allowed Gamow-Teller and Fermi, and first-forbidden ß decays, essential for the understanding of the nucleosynthesis of heavy nuclei in the rapid neutron capture process. Furthermore, the observation of the parity changing 0^{+}→0^{-}ß decay where the daughter state is core excited is unique, and can provide information on mesonic corrections of effective operators.

Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), dsDNA antibodies are associated with renal disease. Less is known about comorbidities in patients without dsDNA or other autoantibodies. Using an electronic health record (EHR) SLE cohort, we employed a phenome-wide association study (PheWAS) that scans across billing codes to compare comorbidities in SLE patients with and without autoantibodies. We used our validated algorithm to identify SLE subjects. Autoantibody status was defined as ever positive for dsDNA, RNP, Smith, SSA and SSB. PheWAS was performed in antibody positive vs. negative SLE patients adjusting for age and race and using a false discovery rate of 0.05. We identified 1097 SLE subjects. In the PheWAS of dsDNA positive vs. negative subjects, dsDNA positive subjects were more likely to have nephritis ( p = 2.33 × 10-9) and renal failure ( p = 1.85 × 10-5). After adjusting for sex, race, age and other autoantibodies, dsDNA was independently associated with nephritis and chronic kidney disease. Those patients negative for dsDNA, RNP, SSA and SSB negative subjects were all more likely to have billing codes for sleep, pain and mood disorders. PheWAS uncovered a hierarchy within SLE-specific autoantibodies with dsDNA having the greatest impact on major organ involvement.

Estimation of radiation risk in presence of classical additive and Berkson multiplicative errors in exposure doses.

In this paper, the influence of measurement errors in exposure doses in a regression model with binary response is studied. Recently, it has been recognized that uncertainty in exposure dose is characterized by errors of two types: classical additive errors and Berkson multiplicative errors. The combination of classical additive and Berkson multiplicative errors has not been considered in the literature previously. In a simulation study based on data from radio-epidemiological research of thyroid cancer in Ukraine caused by the Chornobyl accident, it is shown that ignoring measurement errors in doses leads to overestimation of background prevalence and underestimation of excess relative risk. In the work, several methods to reduce these biases are proposed. They are new regression calibration, an additive version of efficient SIMEX, and novel corrected score methods.

94 ß-Decay Half-Lives of Neutron-Rich _{55}Cs to _{67}Ho: Experimental Feedback and Evaluation of the r-Process Rare-Earth Peak Formation.

The ß-decay half-lives of 94 neutron-rich nuclei ^{144-151}Cs, ^{146-154}Ba, ^{148-156}La, ^{150-158}Ce, ^{153-160}Pr, ^{156-162}Nd, ^{159-163}Pm, ^{160-166}Sm, ^{161-168}Eu, ^{165-170}Gd, ^{166-172}Tb, ^{169-173}Dy, ^{172-175}Ho, and two isomeric states ^{174m}Er, ^{172m}Dy were measured at the Radioactive Isotope Beam Factory, providing a new experimental basis to test theoretical models. Strikingly large drops of ß-decay half-lives are observed at neutron-number N=97 for _{58}Ce, _{59}Pr, _{60}Nd, and _{62}Sm, and N=105 for _{63}Eu, _{64}Gd, _{65}Tb, and _{66}Dy. Features in the data mirror the interplay between pairing effects and microscopic structure. r-process network calculations performed for a range of mass models and astrophysical conditions show that the 57 half-lives measured for the first time play an important role in shaping the abundance pattern of rare-earth elements in the solar system.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Blurring the boundaries: decays of multiparticle isomers at the proton drip line.

A multiparticle spin-trap isomer has been discovered in the proton-unbound nucleus (73)(158)Ta85 . The isomer mainly decays by γ-ray emission with a half-life of 6.1(1) µs. Analysis of the γ-ray data shows that the isomer lies 2668 keV above the known 9+ state and has a spin 10ℏ higher and negative parity. This 19- isomer also has an 8644(11) keV, 1.4(2)% α-decay branch that populates the 9+ state in (154)Lu. No proton-decay branch from the isomer was identified, despite the isomer being unbound to proton emission by 3261(14) keV. This remarkable stability against proton emission is compared with theoretical predictions, and the implications for the extent of observable nuclides are considered.

Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.

Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulin. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.

Marginal longitudinal semiparametric regression via penalized splines.

We study the marginal longitudinal nonparametric regression problem and some of its semiparametric extensions. We point out that, while several elaborate proposals for efficient estimation have been proposed, a relative simple and straightforward one, based on penalized splines, has not. After describing our approach, we then explain how Gibbs sampling and the BUGS software can be used to achieve quick and effective implementation. Illustrations are provided for nonparametric regression and additive models.

Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPARdelta/PGE2 and elevation of PGE3.

We have shown that dietary fish oil and pectin (FP) protects against radiation-enhanced colon cancer by upregulating apoptosis in colonic mucosa. To investigate the mechanism of action, we provided rats (n = 40) with diets containing the combination of FP or corn oil and cellulose (CC) prior to exposure to 1 Gy, 1 GeV/nucleon Fe-ion. All rats were injected with a colon-specific carcinogen, azoxymethane (AOM; 15 mg/kg), 10 and 17 days after irradiation. Levels of colonocyte apoptosis, prostaglandin E(2) (PGE(2)), PGE(3), microsomal prostaglandin E synthase-2 (mPGES-2), total beta-catenin, nuclear beta-catenin staining (%) and peroxisome proliferator-activated receptor delta (PPARdelta) expression were quantified 31 weeks after the last AOM injection. FP induced a higher (P < 0.01) apoptotic index in both treatment groups, which was associated with suppression (P < 0.05) of antiapoptotic mediators in the cyclooxygenase (COX) pathway (mPGES-2 and PGE(2)) and the Wnt/beta-catenin pathway [total beta-catenin and nuclear beta-catenin staining (%); P < 0.01] compared with the CC diet. Downregulation of COX and Wnt/beta-catenin pathways was associated with a concurrent suppression (P < 0.05) of PPARdelta levels in FP-fed rats. In addition, colonic mucosa from FP animals contained (P < 0.05) a proapoptotic, eicosapentaenoic acid-derived COX metabolite, PGE(3). These results indicate that FP enhances colonocyte apoptosis in AOM-alone and irradiated AOM rats, in part through the suppression of PPARdelta and PGE(2) and elevation of PGE(3). These data suggest that the dietary FP combination may be used as a possible countermeasure to colon carcinogenesis, as apoptosis is enhanced even when colonocytes are exposed to radiation and/or an alkylating agent.

Representing Knowledge Consistently Across Health Systems.

Objectives: Electronic health records (EHRs) have increasingly emerged as a powerful source of clinical data that can be leveraged for reuse in research and in modular health apps that integrate into diverse health information technologies. A key challenge to these use cases is representing the knowledge contained within data from different EHR systems in a uniform fashion. Method: We reviewed several recent studies covering the knowledge representation in the common data models for the Observational Medical Outcomes Partnership (OMOP) and its Observational Health Data Sciences and Informatics program, and the United States Patient Centered Outcomes Research Network (PCORNet). We also reviewed the Health Level 7 Fast Healthcare Interoperability Resource standard supporting app-like programs that can be used across multiple EHR and research systems. Results: There has been a recent growth in high-impact efforts to support quality-assured and standardized clinical data sharing across different institutions and EHR systems. We focused on three major efforts as part of a larger landscape moving towards shareable, transportable, and computable clinical data. Conclusion: The growth in approaches to developing common data models to support interoperable knowledge representation portends an increasing availability of high-quality clinical data in support of research. Building on these efforts will allow a future whereby significant portions of the populations in the world may be able to share their data for research.

Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6.

To explore the role of chronically elevated free fatty acids (FFAs) in the pathogenesis of the hyperproinsulinemia of type 2 diabetes, we have investigated the effect of FFAs on proinsulin processing and prohormone convertases PC2 and PC1/PC3 in MIN6 cells cultured in Dulbecco's modified Eagle's medium with or without 0.5 mmol/l FFA mixture (palmitic acid:oleic acid = 1:2). After 7 days of culture, the percent of proinsulin in FFA-exposed cells was increased (25.9 +/-0.3% intracellular and 75.4 +/- 1.2% in medium vs. 13.5 +/-0.2 and 56.2 +/- 4.1%, respectively, in control cells). The biosynthesis and secretion of proinsulin and insulin were analyzed by comparing the incorporation of [3H]Leu and [35S]Met. In pulse-chase studies, proinsulin-to-insulin conversion was inhibited, and proinsulin in the medium was increased by 50% after 3 h of chase, while insulin secretion was decreased by 50% after FFA exposure. Levels of cellular PC2 and PC3 analyzed by Western blotting were decreased by 23 and 15%, respectively. However, PC2, PC3, proinsulin, and 7B2 mRNA levels were not altered by FFA exposure. To test for an effect on the biosynthesis of PC2, PC3, proinsulin, and 7B2, a protein required for PC2 activation, MIN6 cells were labeled with [35S]Met for 10-15 min, followed by a prolonged chase. Most proPC2 was converted after 6 h of chase in control cells, but conversion was incomplete even after 6 h of chase in FFA-exposed MIN6 cells. Media from chase incubations showed that FFA-exposed cells secreted more proPC2 than controls. Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2. In conclusion, prolonged exposure of beta-cells to FFAs may affect the biosynthesis and posttranslational processing of proinsulin, PC2, PC3, and 7B2, and thereby contribute to the hyperproinsulinemia of type 2 diabetes. The mechanism of inhibition of secretory granule processing by FFAs may be through changes in Ca2+ concentration, the pH in the secretory granules, and/or other factors that may influence the activation and function of the convertases.

Lack of islet amyloid polypeptide regulation of insulin biosynthesis or secretion in normal rat islets.

We examined the effects of rat islet amyloid polypeptide (IAPP) on insulin biosynthesis and secretion by isolated rat islets of Langerhans. Culture of islets for 24 h in the presence of 10(-6) M IAPP and 5.5 mM glucose had no effect on insulin mRNA levels. Similarly, the rates of proinsulin biosynthesis were not altered in islets incubated in 10(-4)-10(-9) M IAPP and 5.5 mM glucose, nor was the rate of conversion of proinsulin to insulin changed at 10(-6) M IAPP. Addition of 10(-5) M IAPP to islets incubated in 11 mM glucose decreased the fractional insulin secretion rate; however, the secretion of newly synthesized proinsulin and insulin was not affected. These data indicate that it is unlikely that IAPP is a physiologically relevant modulator of insulin biosynthesis or secretion.

International comparison of waiting times for selected cardiovascular procedures.

OBJECTIVES: This study was designed to compare waiting times for cardiovascular procedures in five different health care delivery/financing systems. BACKGROUND: A recurrent criticism of national health care systems is long waiting times, or "queues," for high technology procedures. However, no objective data exist comparing waiting times in the United States with those in other systems. METHODS: Directors of cardiac catheterization laboratories, directors of cardiac surgery in the United States, U.S. Department of Veterans Affairs (VA) system, Canada and the United Kingdom and directors of cardiology clinics in Sweden were asked to respond to a mailed questionnaire as to how long it would take to obtain coronary angiography or coronary artery bypass surgery, or both, for specified case scenarios at their institutions. RESULTS: Significant differences in waiting times (p < 0.00001) were found among the systems for all four scenarios (elective and urgent angiography, elective and urgent bypass surgery). Compared with non-VA hospitals in the United States, waiting times were significantly longer in all systems, with the exception of waiting times for urgent surgery in the U.S. VA hospitals (p = 0.9). The longest waiting times for all four procedures were reported in the United Kingdom, Sweden and Canada, with some waiting times for elective procedures > 9 months. CONCLUSIONS: Physicians report that patients treated in health care systems structured differently from the non-VA hospital system in the United States wait significantly longer for cardiac catheterization and coronary artery bypass surgery.

Weights for data related by a tree.

How can one characterize a set of data collected from different biological species, or indeed any set of data related by an evolutionary tree? The structure imposed by the tree implies that the data are not independent, and for most applications this should be taken into account. We describe strategies for weighting the data that circumvent some of the problems of dependency.

Turbulent blood flow in the ascending aorta of dogs.

A conical hot film anemometer probe was used to measure instantaneous velocities in the ascending aorta of anaesthetised, open-chest dogs. The probe was mounted on a saddle which allowed traversal of the aorta in 1 mm increments 4 cm above the aortic valve. From these point measurements, the radial distribution of velocity was obtained by averaging ten cardiac cycles. The contractile state of the heart was increased by sequential intravenous infusions of isoprenaline. The absolute peak centreline velocity in the baseline state ranged from 28 to 56 cm x s-1 and, in 20 micrograms x min-1 isoprenaline infusion, from 39 to 112 cm x s-1. Two major effects of isoprenaline on blood flow were noted: 1) isoprenaline dramatically increased peak centreline velocity, and 2) disturbances resembling turbulence appeared as peak velocity increased. With isoprenaline infusion disturbances existed throughout the deceleration portion of the aortic blood flow. Analysis of the frequency components of the velocity wave was performed, and significantly higher frequency components up to 100 Hertz were found in the turbulent cases compared to the laminar ones. Turbulent flow or disturbed flow is found when the ratio of Reynolds number to Womersley number is above 200. In general the hot film measurements showed that both laminar and disturbed velocity profiles tended to be flat throughout the cardiac cycle, with the sharp velocity gradient confined to the region of the wall. Turbulent normal stress during the deceleration portion of aortic blood flow were found in the orders of 15 to 30 dynes x cm-2 and the wall shear stresses were found to be from 10 dynes x cm-2 at the baseline condition to 50 dynes x cm-2 during the 20 micrograms x min-1 isoprenaline infusion.

Genomic profiles and predictive biological networks in oxidant-induced atherogenesis.

Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis.

Statistical design of calibration studies.

We investigated some design aspects of calibration studies. The specific situation addressed was one in which a large group is evaluated with a food-frequency questionnaire and a smaller calibration study is conducted through use of repeated food records or recalls, with the subjects in the calibration study constituting a random sample of those in the large group. In designing a calibration study, one may use large sample sizes and few food records per individual or smaller samples and more records per subject. Neither strategy is always preferable. Instead, the optimal method for a given study depends on the survey instrument used (24-h recalls or multiple-day food records) and the variables of interest.

Dietary fish oil reduces O6-methylguanine DNA adduct levels in rat colon in part by increasing apoptosis during tumor initiation.

There is epidemiological, clinical, and experimental evidence that dietary fish oil, containing n-3 polyunsaturated fatty acids, protects against colon tumor development. However, its effects on colonocytes in vivo remain poorly understood. Therefore, we investigated the ability of fish oil to modulate colonic methylation-induced DNA damage, repair, and deletion. Sprague Dawley rats were provided with complete diets containing either corn oil or fish oil (15% by weight). Animals were injected with azoxymethane, and the distal colon was removed 3, 6, 9, or 12 h later. Targeted apoptosis and DNA damage were assessed by cell position within the crypt using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay and quantitative immunohistochemical analysis of O6-methylguanine adducts, respectively. Localization and expression of the alkyl group acceptor, O6-methylguanine-DNA-methyltransferase, was also determined. Lower levels of adducts were detected at 6, 9, and 12 h in fish oil- versus corn oil-fed animals (P < 0.05). In addition, fish oil supplementation had the greatest effect on apoptosis in the top one-third of the crypt, increasing the apoptotic index compared with corn oil-fed rats (P < 0.05). In the top one-third of the crypt, fish oil feeding caused an incremental stimulation of apoptosis as adduct level increased. In contrast, a negative correlation between apoptosis and adduct incidence occurred with corn oil feeding (P < 0.05). Diet had no main effect (all tertiles combined) on O6-methylguanine-DNA-methyltransferase expression over the time frame of the experiment. The enhancement of targeted apoptosis combined with the reduced formation of O6-methylguanine adducts may account, in part, for the observed protective effect of n-3 polyunsaturated fatty acids against experimentally induced colon cancer.

The joint associations of multiple risk factors with the occurrence of nosocomial infection.

To compare nosocomial infection rates estimated in different time periods or in different hospitals, it is necessary to control for differences in the distribution of factors that substantially influence a patient's susceptibility to infection. To evaluate the associations of multiple risk factors with the occurrence of infection at each of four major sites and to develop composite measures for use in controlling for differences in the distribution of risk among groups of patients, we used a multivariate categorical data analysis technique to study the infection experience of 169,518 patients admitted in 1970 to the 338 hospitals studied in the Study on the Efficacy of Nosocomial Infection Control (SENIC, Project). The relative importance of risk factors and their complex interactions varied by site. The factors found to be highly important for one or more sites were duration of urinary catheterization, the patients' intrinsic risk as reflected in their diagnoses and types of surgical procedures, duration of preoperative hospitalization, duration of operation, anatomic location of surgical procedure, previous infection and steroid or immunosuppressive therapy. Site-specific risk strata and estimates of each patient's probability of acquiring infection were developed from these data for use in future SENIC analyses.

Mitral valve prolapse in coronary artery disease.

Mitral valve motion, left ventricular segmental contraction and severity of arterial stenosis were analyzed in 92 patients with coronary artery disease and 28 patients with "atypical chest pain" and normal coronary arterio-rams. Mitral valve motion was evaluated for the presence or absence of leaflet prolapse. Segmental contraction was evaluated by calculating the percent shortening of six chords of the left ventricle measured from right anterior oblique ventriculograms. The severity of disease in each coronary vessel (left anterior descending, left circumflex and right coronary) was graded on a scale of 1 (0 to 30 percent stenosis) to 5 (complete occlusion). Mitral valve prolapse was not suspected clinically but observed angiographically in 15 of 92 patients with coronary artery disease and in 5 of 28 patients with normal coronary arteriograms. In nine patients with coronary artery disease, the prolapse was restricted to the posterior leaflet, in five it was in both the anterior and the posterior leaflets and in one patient in the anterior leaflet only. Mitral regurgitation was noted in seven patients with coronary artery disease; it was mild in six and moderate in one. Among the patients with coronary artery disease, 12 of the 15 (80 percent) with mitral valve prolapse had left ventricular asynergy compared with 63 of the 77 (82 percent) without valve prolapse. The mean scores for severity of disease in the left anterior descending, circumflex and right coronary arteries were, respectively, 4.2, 2.5 and 3.2 in the patients with valve prolapse and 4.2, 2.2 and 3.5 in those without prolapse. In summary, there was no significant correlation between mitral valve prolapse and distribution of coronary arterial obstructions or abnormal patterns of left ventricular segmental contraction. There was a high frequency of mitral valve prolapse in patients with severe coronary artery disease and in those with normal coronary arteriograms and atypical chest pain.