First-trimester or second-trimester screening, or both, for Down's syndrome

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters.METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency).RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening.CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates

Dipolar collisions of polar molecules in the quantum regime

Ultracold polar molecules offer the possibility of exploring quantum gases with interparticle interactions that are strong, long-range, and spatially anisotropic. This is in stark contrast to the dilute gases of ultracold atoms, which have isotropic and extremely short-range, or "contact", interactions. The large electric dipole moment of polar molecules can be tuned with an external electric field; this provides unique opportunities such as control of ultracold chemical reactions, quantum information processing, and the realization of novel quantum many-body systems. In spite of intense experimental efforts aimed at observing the influence of dipoles on ultracold molecules, only recently have sufficiently high densities been achieved. Here, we report the observation of dipolar collisions in an ultracold molecular gas prepared close to quantum degeneracy. For modest values of an applied electric field, we observe a dramatic increase in the loss rate of fermionic KRb molecules due to ultrcold chemical reactions. We find that the loss rate has a steep power-law dependence on the induced electric dipole moment, and we show that this dependence can be understood with a relatively simple model based on quantum threshold laws for scattering of fermionic polar molecules. We directly observe the spatial anisotropy of the dipolar interaction as manifested in measurements of the thermodynamics of the dipolar gas. These results demonstrate how the long-range dipolar interaction can be used for electric-field control of chemical reaction rates in an ultracold polar molecule gas. The large loss rates in an applied electric field suggest that creating a long-lived ensemble of ultracold polar molecules may require confinement in a two-dimensional trap geometry to suppress the influence of the attractive dipolar interactions

Microwave amplification with nanomechanical resonators

Sensitive measurement of electrical signals is at the heart of modern science and technology. According to quantum mechanics, any detector or amplifier is required to add a certain amount of noise to the signal, equaling at best the energy of quantum fluctuations. The quantum limit of added noise has nearly been reached with superconducting devices which take advantage of nonlinearities in Josephson junctions. Here, we introduce a new paradigm of amplification of microwave signals with the help of a mechanical oscillator. By relying on the radiation pressure force on a nanomechanical resonator, we provide an experimental demonstration and an analytical description of how the injection of microwaves induces coherent stimulated emission and signal amplification. This scheme, based on two linear oscillators, has the advantage of being conceptually and practically simpler than the Josephson junction devices, and, at the same time, has a high potential to reach quantum limited operation. With a measured signal amplification of 25 decibels and the addition of 20 quanta of noise, we anticipate near quantum-limited mechanical microwave amplification is feasible in various applications involving integrated electrical circuits.Comment: Main text + supplementary information. 14 pages, 3 figures (main text), 18 pages, 6 figures (supplementary information

Controlling the quantum stereodynamics of ultracold bimolecular reactions

Chemical reaction rates often depend strongly on stereodynamics, namely the orientation and movement of molecules in three-dimensional space. An ultracold molecular gas, with a temperature below 1 uK, provides a highly unusual regime for chemistry, where polar molecules can easily be oriented using an external electric field and where, moreover, the motion of two colliding molecules is strictly quantized. Recently, atom-exchange reactions were observed in a trapped ultracold gas of KRb molecules. In an external electric field, these exothermic and barrierless bimolecular reactions, KRb+KRb -> K2+Rb2, occur at a rate that rises steeply with increasing dipole moment. Here we show that the quantum stereodynamics of the ultracold collisions can be exploited to suppress the bimolecular chemical reaction rate by nearly two orders of magnitude. We use an optical lattice trap to confine the fermionic polar molecules in a quasi-two-dimensional, pancake-like geometry, with the dipoles oriented along the tight confinement direction. With the combination of sufficiently tight confinement and Fermi statistics of the molecules, two polar molecules can approach each other only in a "side-by-side" collision, where the chemical reaction rate is suppressed by the repulsive dipole-dipole interaction. We show that the suppression of the bimolecular reaction rate requires quantum-state control of both the internal and external degrees of freedom of the molecules. The suppression of chemical reactions for polar molecules in a quasi-two-dimensional trap opens the way for investigation of a dipolar molecular quantum gas. Because of the strong, long-range character of the dipole-dipole interactions, such a gas brings fundamentally new abilities to quantum-gas-based studies of strongly correlated many-body physics, where quantum phase transitions and new states of matter can emerge.Comment: 19 pages, 4 figure

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Improvements in survival of the uncemented Nottingham Total Shoulder prosthesis: a prospective comparative study

<p>Abstract</p> <p>Background</p> <p>The uncemented Nottingham Total Shoulder Replacement prosthesis system (Nottingham TSR) was developed from the previous BioModular^®shoulder prosthesis taking into consideration the causes of the initial implant's failure.</p> <p>We investigated the impact of changes in the design of Nottingham TSR prosthesis on its survivorship rate.</p> <p>Methods</p> <p>Survivorship analyses of three types of uncemented total shoulder arthroplasty prostheses (BioModular^®, initial Nottingham TSR and current Nottingham TSR systems with 11, 8 and 4 year survivorship data respectively) were compared. All these prostheses were implanted for the treatment of disabling pain in the shoulder due to primary and secondary osteoarthritis or rheumatoid arthritis. Each type of the prosthesis studied was implanted in consecutive group of patients – 90 patients with BioModular^®system, 103 with the initial Nottingham TSR and 34 patients with the current Nottingham TSR system.</p> <p>The comparison of the annual cumulative survivorship values in the compatible time range between the three groups was done according to the paired <it>t </it>test.</p> <p>Results</p> <p>The 8-year and 11-year survivorship rates for the initially used modified BioModular^®uncemented prosthesis were relatively low (75.6% and 71.7% respectively) comparing to the reported survivorship of the conventional cemented implants. The 8-year survivorship for the uncemented Nottingham TSR prosthesis was significantly higher (81.8%), but still not in the desired range of above 90%, that is found in other cemented designs. Glenoid component loosening was the main factor of prosthesis failure in both prostheses and mainly occurred in the first 4 postoperative years. The 4-year survivorship of the currently re-designed Nottingham TSR prosthesis, with hydroxylapatite coating of the glenoid baseplate, was significantly higher, 93.1% as compared to 85.1% of the previous Nottingham TSR.</p> <p>Conclusion</p> <p>The initial Nottingham shoulder prosthesis showed significantly higher survivorship than the BioModular^®uncemented prosthesis, but lower than expected. Subsequently re-designed Nottingham TSR system presented a high short term survivorship rate that encourages its ongoing use</p

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. Methods and Findings: A5164 was a randomized strategy trial of ‘‘early ART’’ - given within 14 days of starting acute OI treatment versus ‘‘deferred ART’’ - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) [greater than or equal to] 50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications

Evaluation of sit-stand workstations in an office setting: A randomised controlled trial

Background: Excessive sitting time is a risk factor for cardiovascular disease mortality and morbidity independent of physical activity. This aim of this study was to evaluate the impact of a sit-stand workstation on sitting time, and vascular, metabolic and musculoskeletal outcomes in office workers, and to investigate workstation acceptability and feasibility. Methods: A two-arm, parallel-group, individually randomised controlled trial was conducted in one organisation. Participants were asymptomatic full-time office workers aged ≥18 years. Each participant in the intervention arm had a sit-stand workstation installed on their workplace desk for 8 weeks. Participants in the control arm received no intervention. The primary outcome was workplace sitting time, assessed at 0, 4 and 8 weeks by an ecological momentary assessment diary. Secondary behavioural, cardiometabolic and musculoskeletal outcomes were assessed. Acceptability and feasibility were assessed via questionnaire and interview. ANCOVA and magnitude-based inferences examined intervention effects relative to controls at 4 and 8 weeks. Participants and researchers were not blind to group allocation. Results: Forty-seven participants were randomised (intervention n = 26; control n = 21). Relative to the control group at 8 weeks, the intervention group had a beneficial decrease in sitting time (-80.2 min/8-h workday (95 % CI = -129.0, -31.4); p = 0.002), increase in standing time (72.9 min/8-h workday (21.2, 124.6); p = 0.007) and decrease in total cholesterol (-0.40 mmol/L (-0.79, -0.003); p = 0.049). No harmful changes in musculoskeletal discomfort/pain were observed relative to controls, and beneficial changes in flow-mediated dilation and diastolic blood pressure were observed. Most participants self-reported that the workstation was easy to use and their work-related productivity did not decrease when using the device. Factors that negatively influenced workstation use were workstation design, the social environment, work tasks and habits. Conclusion: Short-term use of a feasible sit-stand workstation reduced daily sitting time and led to beneficial improvements in cardiometabolic risk parameters in asymptomatic office workers. These findings imply that if the observed use of the sit-stand workstations continued over a longer duration, sit-stand workstations may have important ramifications for the prevention and reduction of cardiometabolic risk in a large proportion of the working population. Trial registration: ClinicalTrials.gov NCT02496507