How COVID-19 impacted people with disabilities: A qualitative study in Delaware.

Objectives: The COVID-19 pandemic created unprecedented challenges for people with disabilities and their caregivers and service providers. An assessment of how the COVID-19 pandemic, and the public health response to it, inequitably impacted the health and well-being of people with disabilities is needed to improve preparedness for future public health emergencies. Interviews were conducted with the goal of documenting the impacts of COVID-19 on community-dwelling individuals in Delaware. Study design: Qualitative interviews using a structured interview guide. Methods: In November and December 2022, interviews were conducted with individuals with disabilities, their caregivers, governmental and non-profit service providers, and elected representatives in Delaware. Interviews focused on obtaining information related to COVID-related threats to maintaining good health, affordable and accessible housing, work, educational opportunities, transportation, and community belonging during the pandemic. Interview transcripts were inductively analyzed. Results: Five themes were identified including changes to, or loss of, home-based medical and other services, changes in daily routines that impacted access to work and education, limits on access to transportation, financial strains and housing issues, and mental health concerns. Conclusions: The COVID-19 pandemic impacted nearly all aspects of the lives of people with disabilities. COVID-19 presented long-term, existential threats to progress made toward independent living, meaningful work, and financial, health, and educational equity for people with disabilities.

The World Rugby and International Rugby Players Contact Load Guidelines: From conception to implementation and the future.

Managing training load in rugby union is crucial for optimising performance and injury prevention. Contact training warrants attention because of higher overall injury and head impact risk, yet players must develop physical, technical, and mental skills to withstand the demands of the game. To help coaches manage contact loads in professional rugby, World Rugby and International Rugby Players convened an expert working group. They conducted a global survey with players to develop contact load guidelines. This commentary aims to describe the contact load guidelines and their implementation, and identify areas where future work is needed to support their evolution.

Quasi One-Dimensional Metal-Semiconductor Heterostructures.

The band offsets occurring at the abrupt heterointerfaces of suitable material combinations offer a powerful design tool for high performance or even new kinds of devices. Because of a large variety of applications for metal-semiconductor heterostructures and the promise of low-dimensional systems to present exceptional device characteristics, nanowire heterostructures gained particular interest over the past decade. However, compared to those achieved by mature two-dimensional processing techniques, quasi one-dimensional (1D) heterostructures often suffer from low interface and crystalline quality. For the GaAs-Au system, we demonstrate exemplarily a new approach to generate epitaxial and single crystalline metal-semiconductor nanowire heterostructures with atomically sharp interfaces using standard semiconductor processing techniques. Spatially resolved Raman measurements exclude any significant strain at the lattice mismatched metal-semiconductor heterojunction. On the basis of experimental results and simulation work, a novel self-assembled mechanism is demonstrated which yields one-step reconfiguration of a semiconductor-metal core-shell nanowire to a quasi 1D axially stacked heterostructure via flash lamp annealing. Transmission electron microscopy imaging and electrical characterization confirm the high interface quality resulting in the lowest Schottky barrier for the GaAs-Au system reported to date. Without limiting the generality, this novel approach will open up new opportunities in the syntheses of other metal-semiconductor nanowire heterostructures and thus facilitate the research of high-quality interfaces in metal-semiconductor nanocontacts.

Nucleation of Ga droplets on Si and SiOx surfaces.

We report on gallium droplet nucleation on silicon (100) substrates with and without the presence of the native oxide. The gallium deposition is carried out under ultra-high vacuum conditions at temperatures between 580 and 630 °C. The total droplet volume, obtained from a fit to the diameter-density relation, is used for sample analysis on clean silicon surfaces. Through a variation of the 2D equivalent Ga thickness, the droplet diameter was found to be between 250-1000 nm. Longer annealing times resulted in a decrease of the total droplet volume. Substrate temperatures of 630 °C and above led to Ga etching into the Si substrates and caused Si precipitation around the droplets. In contrast, we obtained an almost constant diameter distribution around 75 nm over a density range of more than two orders of magnitude in the presence of a native oxide layer. Furthermore, the droplet nucleation was found to correlate with the density of surface features on the 'epi-ready' wafer.

Sustained brain activation supporting stop-signal task performance.

Stop-signal paradigms operationalize a basic test of goal-directed behaviour whereby an overarching stop goal that is performed intermittently must be maintained throughout ongoing performance of a reaction time go task (go goal). Previous studies of sustained brain activation during stop-signal task performance in humans did not observe activation of the dorsolateral prefrontal cortex (DLPFC) that, in concert with the parietal cortex, is known to subserve goal maintenance. Here we explored the hypothesis that a DLPFC and parietal network has a key role in supporting ongoing stop-signal task performance. We used a blocked functional magnetic resonance imaging design that included blocks of trials containing typical stop-signal paradigm stimuli that were performed under three conditions: Stop condition, which required reaction time responding to go stimuli and inhibition of cued responses upon presentation of a stop signal; Go condition, identical except that the tone was ignored; and Passive condition, which required only quiescent attention to stimuli. We found that, whereas a distributed corticothalamic network was more active in Stop compared with Go, only the right DLPFC and bilateral parietal cortex survived after masking that contrast with Stop compared with Passive. These findings indicate that sustained activation of a right dominant frontoparietal network supports stop goal processes during ongoing performance of the stop-signal task.

Post pressure hyperemia in the rat.

In prior studies in man, we have demonstrated that pressure-induced hyperemia lasts for prolonged periods as compared to the short-term hyperemia created by proximal arterial occlusion. We have analyzed this phenomenon in our well-studied rat model of skin blood flow. Skin blood flow was measured using laser Doppler techniques in Wistar Kyoto rats at the back, a nutritively perfused site, and at the plantar surface of the paw, where arteriovenous anastomotic perfusion dominates. A customized pressure feedback control device was used to vary applied pressures. At the back, pressures in excess of 80 mmHg resulted in occlusion, whereas at the paw 150 mmHg was required. The peak hyperemic flow after release of pressure was comparable to that elicited by proximal arterial occlusion with a blood pressure cuff. However, the post pressure hyperemia peak descended to a plateau value, which was 50-100% greater than baseline and continued for up to 20 min while the peak following proximal arterial occlusion returned to baseline within 4 min. At the back, post pressure hyperemia reached a maximum after application of 100 mmHg pressure. The application of higher pressures than required for occlusion produced no greater hyperemic response. At the paw, maximum post pressure hyperemia occurred at 100 mmHg, although this pressure level was not totally occlusive. Higher pressures resulted in no greater hyperemia. At the back, 10 min of occlusion produced a maximal peak value whereas 1 min was sufficient at the paw. The application of pressure to a heated probe with subsequent release, produced a hyperemic response. Normalized to baseline blood flow, there was no difference between the hyperemic responses at basal skin temperature and at 44 degrees C. There is a prolonged hyperemic response following local pressure occlusion compared to a much shorter period following proximal ischemic occlusion. One can presume two different mechanisms, one related to ischemia and the other a separate pressure related phenomenon. The thermal vasodilatory response is additive, not synergistic with the post pressure hyperemia we have demonstrated. This finding suggests that different mechanisms are involved in thermal vasodilation and post pressure hyperemia.

Predictors of depression in female adolescents.

Depression during adolescence has been associated with a number of factors, including failure to individuate (Blos, 1968), insecure attachments (Armsden, McCauley, Greenberg, Burke, & Mitchell, 1990), negative parental representations, and object relations that lack self-other differentiation (Blatt, Wein, Chevron, & Quinlan, 1979). The present study examined factors associated with symptoms of depression in 59 nonclinical female adolescents. Specifically, the relationship between a number of theoretically related measures-separation-individuation, interpersonal concerns, self-critical concerns, attachment style, parental representations-and symptoms of depression was investigated. The model developed was able to explain the interrelationships of the variables involved in the psychological process of adolescence, and their demonstrated ability to predict symptoms of depression in normal female adolescents.

Synthesis, structures, and reactivity of weakly coordinating anions with delocalized borate structure: the assessment of anion effects in metallocene polymerization catalysts.

The formation of adducts of tris(pentafluorophenyl)borane with strongly coordinating anions such as CN(-) and [M(CN)(4)](2)(-) (M = Ni, Pd) is a synthetically facile route to the bulky, very weakly coordinating anions [CN[B(C(6)F(5))(3)](2)](-) and [M[CNB(C(6)F(5))(3)](4)](2-) which are isolated as stable NHMe(2)Ph(+) and CPh(3)(+) salts. The crystal structures of [CPh(3)][CN[B(C(6)F(5))(3)](2)] (1), [CPh(3)][ClB(C(6)F(5))(3)] (2), [NHMe(2)Ph](2)[Ni[CNB(C(6)F(5))(3)](4)].2Me(2)CO (4b.2Me(2)CO), [CPh(3)](2)[Ni[CNB(C(6)F(5))(3)](4)].2CH(2)Cl(2) (4c.2CH(2)Cl(2)), and [CPh(3)](2)[Pd[CNB(C(6)F(5))(3)](4)].2CH(2)Cl(2) (5c.2CH(2)Cl(2)) are reported. The CN stretching frequencies in 4 and 5 are shifted by approximately 110 cm(-1) to higher wavenumbers compared to the parent tetracyano complexes in aqueous solution, although the M-C and C-N distances show no significant change on B(C(6)F(5))(3) coordination. Zirconocene dimethyl complexes L(2)ZrMe(2) [L(2) = Cp(2), SBI = rac-Me(2)Si(Ind)(2)] react with 1, 4c or 5c in benzene solution at 20 degrees C to give the salts of binuclear methyl-bridged cations, [(L(2)ZrMe)(2)(mu-Me)][CN[B(C(6)F(5))(3)](2)] and [(L(2)ZrMe)(2)(mu-Me)](2)[M[CNB(C(6)F(5))(3)](4)]. The reactivity of these species in solution was studied in comparison with the known [[(SBI)ZrMe](2)(mu-Me)][B(C(6)F(5))(4)]. While the latter reacts with excess [CPh(3)][B(C(6)F(5))(4)] in benzene to give the mononuclear ion pair [(SBI)ZrMe(+).B(C(6)F(5))(4)(-)] in a pseudo-first-order reaction, k = 3 x 10(-4) s(-1), [(L(2)ZrMe)(2)(mu-Me)][CN[B(C(6)F(5))(3)](2)] reacts to give a mixture of L(2)ZrMe(mu-Me)B(C(6)F(5))(3) and L(2)ZrMe(mu-NC)B(C(6)F(5))(3). Recrystallization of [Cp' '(2)Zr(mu-Me)(2)AlMe(2)][CN[B(C(6)F(5))(3)](2)] affords Cp' '(2)ZrMe(mu-NC)B(C(6)F(5))(3) 6, the X-ray structure of which is reported. The stability of [(L(2)ZrMe)(2)(mu-Me)](+)X(-) decreases in the order X = [B(C(6)F(5))(4)] > [M[CNB(C(6)F(5))(3)](4)] > [CN[B(C(6)F(5))(3)](2)] and increases strongly with the steric bulk of L(2) = Cp(2) << SBI. Activation of (SBI)ZrMe(2) by 1 in the presence of AlBu(i)(3) gives extremely active ethene polymerization catalysts. Polymerization studies at 1-7 bar monomer pressure suggest that these, and by implication most other highly active ethene polymerization catalysts, are strongly mass-transport limited. By contrast, monitoring propene polymerization activities with the systems (SBI)ZrMe(2)/1/AlBu(i)(3) and CGCTiMe(2)/1/AlBu(i)(3) at 20 degrees C as a function of catalyst concentration demonstrates that in these cases mass-transport limitation is absent up to [metal] approximately 2 x 10(-5) mol L(-1). Propene polymerization activities decrease in the order [CN[B(C(6)F(5))(3)](2)](-) > [B(C(6)F(5))(4)](-) > [M[CNB(C(6)F(5))(3)](4)](2-) >> [MeB(C(6)F(5))(3)](-), with differences in activation barriers relative to [CN[B(C(6)F(5))(3)](2)](-) of DeltaDeltaG = 1.1 (B(C(6)F(5))(4)(-)), 4.1 (Ni[CNB(C(6)F(5))(3)](4)(2-)) and 10.7-12.8 kJ mol(-)(1) (MeB(C(6)F(5))(3)(-)). The data suggest that even in the case of very bulky anions with delocalized negative charge the displacement of the anion by the monomer must be involved in the rate-limiting step.

Baseline factors predicting early resumption of driving after life-threatening arrhythmias in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial.

BACKGROUND: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial, patients with ventricular fibrillation or hemodynamically unstable ventricular tachycardia were randomly assigned to receive either an implantable cardioverter-defibrillator (ICD) or antiarrhythmic drug therapy. As part of the trial, patients were asked to participate in a prospective driving survey. The purpose of the survey was to determine what baseline factors and patient characteristics specifically predicted resumption of driving earlier than advised by current guidelines. METHODS: Patients were surveyed anonymously as to their driving habits in the initial period after random assignment and every 6 months thereafter. AVID study coordinators were independently asked to assess their patients' driving status as well. The relation between baseline factors and time to resumption of driving was explored by means of Kaplan-Meier estimates for univariate analyses and the stepwise Cox proportional hazards regression model for multivariate analyses. RESULTS: There were 802 patients who were eligible for assessment of driving status. The majority of patients (58%) resumed driving an automobile within 6 months of their index arrhythmia regardless of whether they received drug therapy or an ICD. By multivariate analysis, patients who were younger than 65 years of age, male, and college educated were more likely to drive early, as were patients whose index arrhythmia was ventricular tachycardia. CONCLUSIONS: Younger, college-educated men and those whose index arrhythmia is ventricular tachycardia are most likely to resume driving <6 months after the initiation of therapy for a potentially life-threatening ventricular arrhythmia. Patients with an ICD did not appear to resume driving later than those who were discharged on antiarrhythmic drugs alone.

Electrical storm presages nonsudden death: the antiarrhythmics versus implantable defibrillators (AVID) trial.

BACKGROUND: Electrical storm, multiple temporally related episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF), is a frequent problem among recipients of implantable cardioverter defibrillators (ICDs). However, insufficient data exist regarding its prognostic significance. METHODS AND RESULTS: This analysis includes 457 patients who received an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial and who were followed for 31 +/- 13 months. Electrical storm was defined as > or = 3 separate episodes of VT/VF within 24 hours. Characteristics and survival of patients surviving electrical storm (n = 90), those with VT/VF unrelated to electrical storm (n = 184), and the remaining patients (n = 183) were compared. The 3 groups differed in terms of ejection fraction, index arrhythmia, revascularization status, and baseline medication use. Survival was evaluated using time-dependent Cox modeling. Electrical storm occurred 9.2 +/- 11.5 months after ICD implantation, and most episodes (86%) were due to VT. Electrical storm was a significant risk factor for subsequent death, independent of ejection fraction and other prognostic variables (relative risk [RR], 2.4; 95% confidence interval [CI], 1.3 to 4.2; P = 0.003), but VT/VF unrelated to electrical storm was not (RR, 1.0; 95% CI, 0.6 to 1.7; P = 0.9). The risk of death was greatest 3 months after electrical storm (RR, 5.4; 95% Cl, 2.4 to 12.3; P = 0.0001) and diminished beyond this time (RR, 1.9; 95% CI, 1.0 to 3.6; P=0.04). CONCLUSIONS: Electrical storm is an important, independent marker for subsequent death among ICD recipients, particularly in the first 3 months after its occurrence. However, the development of VT/VF unrelated to electrical storm does not seem to be associated with an increased risk of subsequent death.

"Stable" ventricular tachycardia is not a benign rhythm : insights from the antiarrhythmics versus implantable defibrillators (AVID) registry.

BACKGROUND: Sustained ventricular tachycardia (VT) can be unstable, can be associated with serious symptoms, or can be stable and relatively free of symptoms. Patients with unstable VT are at high risk for sudden death and are best treated with an implantable defibrillator. The prognosis of patients with stable VT is controversial, and it is unknown whether implantable cardioverter-defibrillator therapy is beneficial. METHODS AND RESULTS: Screening for the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial identified patients with both stable and unstable VT. Both groups were included in a registry, and their clinical characteristics and discharge treatments were recorded. Mortality data were obtained through the National Death Index. The mortality in 440 patients with stable VT tended to be greater than that observed in 1029 patients presenting with unstable VT (33.6% versus 27.6% at 3 years; relative risk [RR]=1.22; P:=0.07). After adjustment for baseline and treatment differences, the RR was little changed (RR=1.25, P:=0.06). CONCLUSIONS: Sustained VT without serious symptoms or hemodynamic compromise is associated with a high mortality rate and may be a marker for a substrate capable of producing a more malignant arrhythmia. Implantable cardioverter-defibrillator therapy may be indicated in patients presenting with stable VT.

Determinants of outcome in patients with sustained ventricular tachyarrhythmias: the antiarrhythmics versus implantable defibrillators (AVID) study registry.

BACKGROUND: The prognosis of patients with sustained ventricular tachyarrhythmias varies according to clinical characteristics. We sought to identify predictors of survival in a large population of patients with documented sustained ventricular tachyarrhythmias not related to reversible or correctable causes included in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Registry. METHODS AND RESULTS: We analyzed the impact of 36 demographic, clinical, and discharge treatment variables on the outcome for 3559 patients. Survival status was assessed with the use of the National Death Index. Multivariate analyses were performed with the use of the Cox proportional hazards model. After a mean follow-up of 17 +/- 12 months, 631 patients died. Actuarial survival was 0.86 (95% confidence interval [CI] 0.85 to 0.88), 0.79 (95% CI 0.78 to 0.81), and 0.72 (95% CI 0.70 to 0.74) at 1, 2, and 3 years. Multivariate predictors of worse survival included older age, severe left ventricular dysfunction, lower systolic blood pressure, history of congestive heart failure, diabetes, smoking or atrial fibrillation, and preexistent pacemaker. The hemodynamic impact of the qualifying arrhythmia was not a predictor of outcome. Defibrillator implantation and hospital discharge while the patient was taking a beta-blocker or an angiotensin-converting enzyme inhibitor were associated with better prognosis. CONCLUSIONS: Despite therapeutic advances, the mortality rates of patients with sustained ventricular tachyarrhythmias remain high. Prognosis depends on the severity of underlying heart disease, as reflected by the extent of left ventricular dysfunction and the presence of heart failure. Well-tolerated ventricular tachycardia in patients with structural heart disease does not carry a significantly better prognosis than ventricular tachyarrhythmia with more severe hemodynamic consequences.

A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the efficacy and tolerability of two recombinant human FSH (r-hFSH) preparations, follitropin-alpha (Gonal-F; Ares Serono, Geneva, Switzerland) and follitropin-beta (Puregon; Organon, Oss, the Netherlands), for superovulation in patients undergoing IVF-ET. DESIGN: Randomized, parallel-group, assessor-blind, single-center trial. SETTING: Outpatient tertiary referral center for assisted reproductive techniques. PATIENT(S): Forty-four infertile women undergoing IVF-ET. INTERVENTION(S): After down-regulation with buserelin acetate, patients were randomized to receive follitropin-alpha or follitropin-beta, 150 IU/d for 6 days; after that, dosages were adjusted according to the ovarian response. MAIN OUTCOME MEASURE(S): Cumulative dose of r-hFSH; duration of r-hFSH treatment; number of follicles of > or =11 mm and of 14 mm on day 7 of r-hFSH treatment and on the day of hCG administration; number of oocytes retrieved; number of viable embryos; and number of pregnancies (biochemical, ectopic, miscarried) and clinical pregnancies. RESULT(S): There were no statistically significant differences in any efficacy measures between the two preparations. The incidence of systemic adverse events was comparable in the two groups. Local reactions at the injection site were significantly more common and more severe with follitropin-beta than with follitropin-alpha CONCLUSION(S): Follitropin-alpha and follitropin-beta have comparable efficacy in patients undergoing IVF-ET.

Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. AVID Investigators. Antiarrhythmics Versus Implantable Defibrillators.

OBJECTIVES: We sought to assess the effect of baseline ejection fraction on survival difference between patients with life-threatening ventricular arrhythmias who were treated with an antiarrhythmic drug (AAD) or implantable cardioverter-defibrillator (ICD). BACKGROUND: The Antiarrhythmics Versus Implantable Defibrillators (AVID) study demonstrated improved survival in patients with ventricular fibrillation or ventricular tachycardia with a left ventricular ejection fraction (LVEF) < or =0.40 or hemodynamic compromise. METHODS: Survival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF < or =0.40 or hemodynamic compromise) were compared at different levels of ejection fraction. RESULTS: In patients with an LVEF > or =0.35, there was no difference in survival between AAD-treated and ICD-treated patients. A test for interaction was not significant, but had low power to detect an interaction. For patients with an LVEF 0.20 to 0.34, there was a significantly improved survival with ICD as compared with AAD therapy. In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as that in the 0.20 to 0.34 LVEF subgroup, but the difference did not reach statistical significance. CONCLUSIONS: These data suggest that patients with relatively well-preserved LVEF (> or =0.35) may not have better survival when treated with the ICD as compared with AADs. At a lower LVEF, the ICD appears to offer improved survival as compared with AADs. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (> or =0.35) on the relative treatment effect of AADs and the ICDs.

In-hospital versus out-of-hospital presentation of life-threatening ventricular arrhythmias predicts survival: results from the AVID Registry. Antiarrhythmics Versus Implantable Defibrillators.

OBJECTIVES: This study describes the outcomes of patients from the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study Registry to determine how the location of ventricular arrhythmia presentation influences survival. BACKGROUND: Most studies of cardiac arrest report outcome following out-of-hospital resuscitation. In contrast, there are minimal data on long-term outcome following in-hospital cardiac arrest. METHODS: The AVID Study was a multicenter, randomized comparison of drug and defibrillator strategies to treat life-threatening ventricular arrhythmias. A Registry was maintained of all patients with sustained ventricular arrhythmias at each study site. The present study includes patients who had AVID-eligible arrhythmias, both randomized and not randomized. Patients with in-hospital and out-of-hospital presentations are compared. Data on long-term mortality were obtained through the National Death Index. RESULTS: The unadjusted mortality rates at one- and two-year follow-ups were 23% and 31.1% for patients with in-hospital presentations, and 10.5% and 16.8% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted mortality rates at one- and two-year follow-ups were 14.8% and 20.9% for patients with in-hospital presentations, and 8.4% and 14.1% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted long-term relative risk for in-hospital versus out-of-hospital presentation was 1.6 (95% confidence interval [CI] 1.3-1.9). CONCLUSIONS: Compared with patients with out-of-hospital presentations of life-threatening ventricular arrhythmias not due to a reversible cause, patients with in-hospital presentations have a worse long-term prognosis. Because location of ventricular arrhythmia presentation is an independent predictor of long-term outcome, it should be considered as an element of risk stratification and when planning clinical trials.

Mechanism of catecholamine-mediated destabilization of messenger RNA encoding Thy-1 protein in T-lineage cells.

The Ig superfamily cell surface glycoprotein Thy-1 expressed on immune cells and neurons of rodents and humans is hypothesized to function in cell adhesion and signal transduction in T cell differentiation, proliferation, and apoptosis. This study analyzes effects of cAMP and catecholamines on transcriptional Thy-1 gene expression. Incubation of murine thymocytes or S49 mouse thymoma cells with dibutyryl-cAMP, 8-bromo-cAMP, cholera toxin, norepinephrine, or isoproterenol caused time- and concentration-dependent decreases in levels of Thy-1 mRNA assayed by Northern hybridization or T2 nuclease protection. After 4 h of treatment with 500 microM dibutyryl-cAMP or 8-bromo-cAMP, 1 nM cholera toxin, 100 microM norepinephrine, or 100 microM isoproterenol, Thy-1 mRNA levels were 60 to 96% lower than those of controls. Norepinephrine-mediated decreases in Thy-1 mRNA levels were prevented by the beta-adrenergic receptor antagonist propranolol (10 microM). Dibutyryl-cAMP and norepinephrine decreased the apparent half-life of S49 cell Thy-1 mRNA from >>6 h to 2 to 3 h, whereas nuclear run-on assays showed no cAMP or norepinephrine effect on de novo transcription of the Thy-1 gene. In mutant S49 cells lacking cAMP-dependent protein kinase A, neither dibutyryl cAMP nor norepinephrine affected Thy-1 mRNA levels. These observations show that exogenous cAMP and norepinephrine can induce decreases in steady state Thy-1 mRNA levels in T-lineage cells through posttranscriptional destabilization of Thy-1 mRNA, associated with protein kinase A-mediated protein phosphorylation. Catecholamine-mediated beta-adrenergic protein kinase A-dependent Thy-1 mRNA destabilization may be an example of a more general mRNA decay system regulating cellular responses to stress.

The analysis of lysergide (LSD): the development of novel enzyme immunoassay and immunoaffinity extraction procedures together with an HPLC-MS confirmation procedure.

A forensic procedure for the screening and confirmation of the presence of lysergide (lysergic acid diethylamide, LSD) in urine is described together with the evaluation of a novel enzyme immunoassay (EIA) and immunoaffinity extraction procedure. Following initial screening using either an established radioimmunoassay (RIA) or a novel EIA procedure, a quantitative estimate is established using a conventional high performance liquid chromatography-fluorescence (HPLC) technique following solid phase extraction. Final confirmation and quantitation, without derivatization, is established using HPLC in combination with electrospray ionization (ESI) mass spectrometry using methysergide as an internal standard. The detection limit of LSD in urine is 0.5 ng/mL. A blind trial confirmed the validity of the results. The choice of internal standard is discussed. Consideration is given to the photosensitivity of LSD solutions. A study of potential interferants in the HPLC-MS confirmation of LSD is presented and shows that for the wide range of compounds studied, there are none that would interfere with this confirmation technique. A comparison is shown between solid phase and immunoaffinity extraction/clean up procedures, and between RIA and EIA screening procedures.

Relation of circadian ventricular ectopic activity to cardiac mortality. CAST Investigators.

The relation between the circadian occurrence of ventricular premature depolarizations (VPD) and sudden arrhythmic death was examined in a subset of patients entered into the Cardiac Arrhythmia Suppression Trial (CAST). Ambulatory electrocardiographic recordings with hourly measurement of VPD frequency were available in 357 patients. Forty percent of the patients (142 of 357) demonstrated circadian variation in VPD frequency between 6:00 A.M. and 9:59 A.M. that was significantly higher (p < 0.05) than what could randomly be expected from an overall 24-hour average for that patient. The only baseline characteristics in patients with circadian VPDs were age (p < 0.04), history of cardiac arrest (p < 0.01), presence of higher frequency of VPDs (p < 0.002), more frequent episodes of ventricular tachycardia (p < 0.04), and more frequent episodes of slow runs (p < 0.04). There was no difference in mortality in patients with or without circadian VPD variation; drug treatment did not effect mortality. These data indicate that the presence of circadian VPDs is not a predictor of sudden arrhythmic death in patients with a high frequency of VPDs.

A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease.

Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.

Clinical trial enrollers vs. nonenrollers: the Cardiac Arrhythmia Suppression Trial (CAST) Recruitment and Enrollment Assessment in Clinical Trials (REACT) project.

The Recruitment and Enrollment Assessment in Clinical Trials (REACT) was a National Heart, Lung, and Blood Institute (NHLBI)-sponsored substudy to the Cardiac Arrhythmia Suppression Trial (CAST). Two-hundred-sixty (260) patients who enrolled in CAST and 140 partially or fully eligible patients who did not enroll were compared across several parameters, including demographic variables, disease severity, psychosocial functioning, health beliefs, recruitment experience, and understanding of informed consent procedures used in CAST. Significant predictors of enrollment included several demographic variables (e.g., being male, not having medical insurance), episodes of ventricular tachycardia, and health beliefs (e.g., extra beats are harmful, a higher degree of general health concern). Enrollment was higher for those who read and understood the informed consent and those who were initially recruited after hospital discharge, particularly nondepressed patients. In the multivariate model, the key variables that emerged were the patient's reading of the informed consent form and the patient's lack of medical insurance. These results suggest that (1) the clinical trial staff's interaction with the patient and the time when recruitment is initiated contribute significantly to the decision to enroll; and (2) it may be a greater challenge to motivate patients to enroll in future clinical trials if health care reform improves access to medical insurance coverage. Some of the significant variables are modifiable, suggesting interventions that may increase enrollment rates in future trials.