Gonadotropin-releasing hormone agonist overuse: urologists' response to reimbursement and characteristics associated with persistent overuse.

BACKGROUND: Medicare reimbursement cuts have been associated with declining gonadotropin-releasing hormone (GnRH) agonist overuse in localized prostate cancer. Medical school affiliation and foreign training have been associated with persistent overuse. However, physician-level prescribing changes and the practice type of persistent overusers have not been examined. We sought to describe physician-level changes in GnRH agonist overuse and test the association of time in practice and solo practice type with GnRH agonist overuse. METHODS: We matched American Medical Association physician data for 2138 urologists to Surveillance, Epidemiology and End Result-Medicare data for 12,943 men diagnosed with early-stage and lower-grade adenocarcinoma of the prostate between 2000 and 2007. We conducted a population-based, retrospective study using multilevel modeling to control for patient and provider characteristics. RESULTS: Three distinct patterns of GnRH agonist overuse were observed. Urologists' time in practice was not associated with GnRH agonist overuse (odds ratio (OR) 0.89; 95% confidence interval (CI): 0.75-1.05). However, solo practice type (OR 1.65; 95% CI: 1.34-2.02), medical school affiliation (OR 0.65; 95% CI: 0.55-0.77) and patient race were. Compared with non-Hispanic whites, non-Hispanic blacks (OR 1.76; 95% CI: 1.37-2.27), Hispanics (OR 1.41; 95% CI: 1.12-1.79) and men of 'other' race (OR 1.44; 95% CI: 1.04-1.99) had greater odds of receiving unnecessary GnRH agonists. CONCLUSIONS: GnRH agonist overuse remains high among some urologists who may be professionally isolated and difficult to reach. These urologists treat more vulnerable populations, which may contribute to health disparities in prostate cancer treatment quality. Nonetheless, these findings provide guidance to develop interventions to address overuse in prostate cancer.

Tokamak operation with safety factor q95 < 2 via control of MHD stability.

Magnetic feedback control of the resistive-wall mode has enabled the DIII-D tokamak to access stable operation at safety factor q(95) = 1.9 in divertor plasmas for 150 instability growth times. Magnetohydrodynamic stability sets a hard, disruptive limit on the minimum edge safety factor achievable in a tokamak, or on the maximum plasma current at a given toroidal magnetic field. In tokamaks with a divertor, the limit occurs at q(95) = 2, as confirmed in DIII-D. Since the energy confinement time scales linearly with current, this also bounds the performance of a fusion reactor. DIII-D has overcome this limit, opening a whole new high-current regime not accessible before. This result brings significant possible benefits in terms of fusion performance, but it also extends resistive-wall mode physics and its control to conditions never explored before. In present experiments, the q(95) < 2 operation is eventually halted by voltage limits reached in the feedback power supplies, not by intrinsic physics issues. Improvements to power supplies and to control algorithms have the potential to further extend this regime.

Soft x-ray array system with variable filters for the DIII-D tokamak.

Recent upgrades to the soft x-ray (SXR) array system on the DIII-D tokamak are described. The system consists of two 32-channel arrays at one toroidal location and three toroidally distributed 12-channel arrays. The 32-channel arrays have been completely rebuilt to allow the switching of SXR filters without breaking vacuum. The 12-channel arrays have had upgrades performed to detectors, view slits, and data acquisition. Absolute extreme ultraviolet (AXUV) photodiodes are used as detectors in all arrays, allowing detection of photons ranging in energy from 2 eV to 10 keV. In the fixed-filter arrays, 127 µm Be filters are used. In the variable-filter arrays, filter wheels are used to switch between five different possible pinhole/filter combinations.

Transcutaneous bilirubin levels in an outpatient and office population.

OBJECTIVE: The use of transcutaneous bilirubin (TcB) measurements has been studied extensively in the newborn population, but there have been few studies in outpatient populations and none from the offices of practicing pediatricians. STUDY DESIGN: We performed TcB measurements on a mixed-race population of 120 jaundiced infants, ≥ 35 weeks of gestation, in two hospital-based outpatient clinics, a regional public health nurse follow-up program and two pediatric office practices. Three individual TcB readings were obtained from the mid-sternum, and the average and maximum values were recorded. RESULT: There was good correlation between the TcB and total serum bilirubin (TSB) measurements (r=0.78, P=0.0). 59% of TSB's were ≥15 mg dl(-1) and, although the number of false-negative readings increased when the TSB values exceeded 15 mg dl(-1), it was nevertheless possible to use TcB measurements to accurately predict the risk of TSB levels ≥ 15 mg dl(-1). CONCLUSION: In outpatient settings, a TcB measurement with the JM-103 provides a reliable screening method for the identification of hyperbilirubinemia even when the TSB level exceeds 15 mg dl(-1). Using the maximum of three independent measurements reduces the number of false negatives, but increases the number of false positives. The use of TcB measurements in an outpatient practice should be a valuable tool for the practitioner.

Implementing evidence-based patient self-management programs in the Veterans Health Administration: perspectives on delivery system design considerations.

While many patient self-management (PSM) programs have been developed and evaluated for effectiveness, less effort has been devoted to translating and systematically delivering PSM in primary and specialty care. Therefore, the purpose of this paper is to review delivery system design considerations for implementing self-management programs in practice. As lessons are learned about implementing PSM programs in Veterans Health Administration (VHA), resource allocation by healthcare organization for formatting PSM programs, providing patient access, facilitating PSM, and incorporating support tools to foster PSM among its consumers can be refined and tailored. Redesigning the system to deliver and support PSM will be important as implementation researchers translate evidence based PSM practices into routine care and evaluate its impact on the health-related quality of life of veterans living with chronic disease.

Evaluation of transcutaneous bilirubinometry in preterm neonates.

OBJECTIVE: To determine the accuracy and precision of transcutaneous bilirubin (TcB) measurements in preterm neonates. STUDY DESIGN: Neonates were stratified into three groups on the basis of gestational age: 24 to 28 weeks (Group 1, n=30), 29 to 31 weeks (Group 2, n=29) and 32 to 34 weeks (Group 3, n=31). TcB was measured using the Draeger Air Shields JM-103, and when possible, measurements were made by two observers. TcB and total serum bilirubin (TSB) measurements were compared, and interobserver precision for TcB measurements was assessed. RESULT: Correlations between TcB and TSB ranged from 0.79 to 0.92. Most of the differences between TcB and TSB were +/-2 mg per 100 ml, and there was no trend for the difference to increase with increasing bilirubin values. Sensitivity, specificity and negative predictive values ranged from 0.67 to 1.0, 0.29 to 0.81 and 0.60 to 1.0, respectively. Intraclass correlations were 0.87 to 0.92. CONCLUSION: TcB correlates significantly with TSB in preterm neonates, and interobserver precision is significant. Routine measurement of TcB in preterm neonates may provide enhanced clinical monitoring for hyperbilirubinemia.

Observation of plasma rotation driven by static nonaxisymmetric magnetic fields in a tokamak.

We present the first evidence for the existence of a neoclassical toroidal rotation driven in a direction counter to the plasma current by nonaxisymmetric, nonresonant magnetic fields. At high beta and with large injected neutral beam momentum, the nonresonant field torque slows down the plasma toward the neoclassical "offset" rotation rate. With small injected neutral beam momentum, the toroidal rotation is accelerated toward the offset rotation, with resulting improvement in the global energy confinement time. The observed magnitude, direction, and radial profile of the offset rotation are consistent with neoclassical theory predictions.

Reduced critical rotation for resistive-wall mode stabilization in a near-axisymmetric configuration.

Recent DIII-D experiments with reduced neutral beam torque and minimum nonaxisymmetric perturbations of the magnetic field show a significant reduction of the toroidal plasma rotation required for the stabilization of the resistive-wall mode (RWM) below the threshold values observed in experiments that apply nonaxisymmetric magnetic fields to slow the plasma rotation. A toroidal rotation frequency of less than 10 krad/s at the q=2 surface (measured with charge exchange recombination spectroscopy using C VI) corresponding to 0.3% of the inverse of the toroidal Alfvén time is sufficient to sustain the plasma pressure above the ideal MHD no-wall stability limit. The low-rotation threshold is found to be consistent with predictions by a kinetic model of RWM damping.

Evaluation of a point-of-care direct spectrophotometric method for measurement of total serum bilirubin in term and near-term neonates.

OBJECTIVE: To evaluate point-of-care (POC) measurement of total serum bilirubin (TSB) in the management of neonatal jaundice. STUDY DESIGN: TSB was measured by a POC direct spectrophotometric bilirubin method (Unistat (U/TSB)) and a standard diazo clinical laboratory method (Olympus AU640E analyzer (diazo/TSB)). Agreement between U/TSB and diazo/TSB was assessed by correlation coefficient and Bland-Altman analysis. Transcutaneous bilirubin (TcB) was measured using JM-103 (JM). RESULTS: Correlation between U/TSB and diazo/TSB was 0.99 (n = 120). Maximum difference (U/TSB minus diazo/TSB) was -2.9 mg/dl, and 79% were +/-1 mg/dl; the average difference was -0.37+/-0.70 mg/dl and the average absolute difference was 0.60+/-0.52 mg/dl. Median time to determine U/TSB was 5 min. Correlation between U/TSB and JM was 0.92 (n = 113). Maximum difference (U/TSB minus JM) was 6.3 mg/dl, and 45% were +/-1 mg/dl; the average difference was 0.7+/-1.8 mg/dl and the average absolute difference was 1.4+/-1.2 mg/dl. CONCLUSION: Measurement of TSB using Unistat provides excellent agreement with diazo/TSB and rapid turnaround time. This technique may provide reliable POC confirmation of TcB results that are above a screening cutoff value.

Measurement of the resistive-wall-mode stability in a rotating plasma using active MHD spectroscopy.

The stability of the resistive-wall mode (RWM) in DIII-D plasmas above the conventional pressure limit, where toroidal plasma rotation in the order of a few percent of the Alfve n velocity is sufficient to stabilize the n=1 RWM, has been probed using the technique of active MHD spectroscopy at frequencies of a few Hertz. The measured frequency spectrum of the plasma response to externally applied rotating resonant magnetic fields is well described by a single-mode approach and provides an absolute measurement of the damping rate and the natural mode rotation frequency of the stable RWM.

Gamma-aminobutyric acid (GABA) regulation of GnRH secretion in sheep.

The frequency and amplitude of GnRH and LH pulses are variable and controlled by both external environmental and internal physiological factors. However, the specific neurochemical-neuroanatomical pathways that control the basal pulsatile and surge patterns, and mediate responses to environmental and physiological factors are poorly defined. The gamma-aminobutyric acid (GABA) secretory system is one of several that modulate GnRH and LH. GABA release in the preoptic area (POA) preceding the onset of oestrogen-induced LH surges changes in a pattern that is inverse to LH release. Application of GABA agonists or antagonists to either the POA or mediobasal hypothalamus disrupts LH secretion. Observations that application of GABA(B) agonists to either the POA or mediobasal hypothalamus rapidly reverses the negative feedback effect of oestrogen or testosterone on LH lead the authors to suggest that GABA(B) receptors have an important role in regulating LH secretion in sheep.

Acyclovir suppression to prevent recurrent genital herpes at delivery.

OBJECTIVE: To determine if suppressive acyclovir near term decreased the frequency of clinical recurrences at delivery in women with recurrent genital herpes simplex virus (HSV) infection. METHODS: We conducted a prospective, double-blind, randomized trial in 234 women with recurrent genital herpes. Women with genital infection of any frequency were enrolled. Patients received either suppressive oral acyclovir 400 mg three times daily or an identical placebo after 36 weeks' gestation. Clinical lesions were identified, and HSV cultures were obtained at delivery. The frequencies of clinical and subclinical HSV recurrences at delivery were evaluated. RESULTS: Six percent of patients treated with acyclovir, and 14% of patients treated with placebo had clinical HSV at delivery (p = 0.046). No patients in the acyclovir group had positive HSV cultures, compared with 6% of placebo-treated patients (p = 0.029). There was no significant difference in subclinical HSV shedding in the acyclovir group (0%) compared with the placebo-treated group (3%) (p = 0.102). CONCLUSIONS: Suppressive acyclovir therapy significantly decreased the incidence of clinical genital herpes and the overall incidence of HSV excretion at delivery in patients with previous herpes infection.

Acyclovir suppression to prevent clinical recurrences at delivery after first episode genital herpes in pregnancy: an open-label trial.

OBJECTIVE: To continue evaluation of the use of acyclovir suppression in late pregnancy after first episode genital herpes simplex virus (HSV) infection, using an open-label study design. METHODS: Ninety-six women diagnosed with genital herpes for the first time in the index pregnancy were prescribed suppressive acyclovir 400 mg orally three times daily from 36 weeks until delivery in an open-label fashion. Herpes cultures were obtained when patients presented for delivery. Vaginal delivery was permitted if no clinical recurrence was present; otherwise a Cesarean delivery was performed. Neonatal HSV cultures were obtained and infants were followed clinically. Rates of clinical and asymptomatic genital herpes recurrences and Cesarean delivery for genital herpes were measured, and 95% confidence intervals were calculated. RESULTS: In 82 patients (85%) compliant with therapy, only 1% had clinical HSV recurrences at delivery. In an intent to treat analysis of the entire cohort, 4% had clinical recurrences (compared with 18-37% in historical controls). Asymptomatic shedding occurred in 1% of women without lesions at delivery. Two of the four clinical recurrences were HSV-culture positive. No significant maternal or fetal side-effects were observed. CONCLUSIONS: In clinical practice the majority of patients are compliant with acyclovir suppression at term. The therapy appears to be effective at reducing clinical recurrences after a first episode of genital herpes complicating a pregnancy.

Problem identification in apparently well neonates: implications for early discharge.

The frequency, time of identification, and type of problems of newborns in an urban indigent population were prospectively studied during their hospital stay to evaluate feasibility of early hospital discharge. Eight percent (563) of 7,021 term and near-term low-risk infants developed one or more predefined problems. Of those with problems, 42.1% received therapy and/or a higher level of care. Tachypnea, temperature instability, and cyanotic episodes were the most frequently treated problems. Nearly 69% of all problems were detected after the initial examination, and 31% developed problems after 24 hours of age; 5% were transferred to the NICU. Problems occurring after 24 hours of age emphasize the need for follow-up within days after hospital discharge in this population.

Neonatal pneumonia: comparison of 4 vs 7 days of antibiotic therapy in term and near-term infants.

OBJECTIVE: To compare a 4-day course of antibiotic therapy to a 7-day course in selected term and near-term neonates with pneumonia. METHODS: The diagnosis of pneumonia was made in neonates admitted to the normal Newborn Nursery (NBN) who later had signs of respiratory distress and whose chest radiographs were consistent with pneumonia. Infants were excluded if any of the following was present: moderate or thick meconium-stained amniotic fluid, prior antibiotic therapy > 24 hours, or need for supplemental oxygen > 8 hours. Infants who were asymptomatic after 48 hours of antibiotic therapy were prospectively randomized to a 4-day group (n = 35) or a 7-day group (n = 38). Infants in the 4-day group were observed in the hospital for 24 hours following cessation of antibiotics and were seen in follow up within several days of discharge. RESULTS: The groups were comparable with regard to demographic factors, duration of rupture of membranes, and incidence of maternal chorioamnionitis. Median postnatal age at the time of identification of respiratory distress symptomatology was 19 hours (range 0.5 to 55 hours) in the 4-day group and 12 hours (range 1 to 72 hours) in the 7-day group. No study infants had a positive blood culture. Mean reduction in length of hospitalization was 2.1 days, with estimated savings of greater than US$700 per shortened hospitalization. Two infants in the 4-day group developed tachypnea during the 24-hour observation period. However, no infants were rehospitalized for sepsis or pneumonia following discharge. With 95% confidence, the true rate of success for the 4-day group was at least 92%. CONCLUSION: Four days of antibiotic therapy plus a 24-hour period of observation for selected cases of neonatal pneumonia appears to be comparable to 7 days of therapy. It is important to note that newborns in our institution receive a single dose of penicillin soon after birth as part of our group B streptococcal sepsis prophylaxis program, and all infants in this study received prophylaxis prior to the onset of respiratory symptoms. Furthermore, only infants who were asymptomatic after 48 hours of antibiotic therapy were included in this study, and a 24-hour observation period at the end of the 4-day course was required. These qualifications should be taken into account before use of this approach is considered, and additional studies are necessary to further establish its safety and benefits.

A gamma-aminobutyric acidB agonist reverses the negative feedback effect of testosterone on gonadotropin-releasing hormone and luteinizing hormone secretion in the male sheep.

Infusion of baclofen, a GABA(B) agonist, into the medial basal hypothalamus (MBH) of castrated rams rapidly increases LH pulse amplitude without altering pulse frequency. The objectives of this study were to determine whether baclofen infusion increased LH in testosterone (T)-treated and intact rams, the increased LH was due to increased GnRH release, and FSH secretion also was increased. In the first experiment we tested the main effects and interaction of baclofen and T on FSH and LH pulse patterns in castrated rams (n = 7). In the second experiment we determined whether baclofen affected GnRH and LH pulses in intact males. Microdialysis guide cannulae were implanted bilaterally into the MBH. After recovery of the animal from surgery, the MBH was perfused using concentric microdialysis probes (2-mm tip) with artificial cerebrospinal fluid (aCSF) for a 3-h control period followed by either aCSF or 1 mM baclofen for 4 h. Blood samples were taken at 10-min intervals. T suppressed mean LH concentrations (10.4 +/- 1.3 vs. 3.3 +/- 1.3 ng/ml) such that LH pulses were undetectable in some T-treated animals during the control period. The change (control period vs. drug infusion period) in mean LH was greater in response to baclofen than in response to aCSF and was not altered by T. The baclofen x T interaction was nonsignificant. Mean FSH was decreased by T, but was not altered by baclofen. In the second experiment hypophyseal portal blood was collected coincident with microdialysis. Infusion of baclofen into the MBH of intact males (n = 7) resulted within 1 h in the onset of frequent and robust GnRH pulses (0.10/h before baclofen vs. 1.57/h after baclofen) that were followed either immediately or gradually by coincident LH pulses. One interpretation is that baclofen acts downstream of the site of action of T. GABA(B) receptors may regulate pulse amplitude in both the presence and absence of T and regulate pulse frequency by modulating the inhibitory effect of T.

Interactions of photoperiod, testosterone, and naloxone on GnRH and LH pulse parameters in the male sheep.

This study tested the hypothesis that the effects of the opiate antagonist naloxone on GnRH (and LH) secretion is affected by photoperiod length and testosterone (T) concentrations. The effect of infusing naloxone on GnRH and LH pulse patterns was determined in four groups of orchidectomized sheep: long day (LD) photoperiod treated with T, LD without T (LDC), short day photoperiod (SD) with T, SDC (n = 5-7/group). Hypophyseal-portal and jugular blood samples were collected at 10 min intervals for 4 h before and 4 h during naloxone infusion (1 mg/kg/h). Neither photoperiod nor T affected either mean GnRH or LH whereas naloxone (P < 0.01) increased both. LD photoperiod (P < 0.01), T (P < 0.01) and naloxone (P < 0.01) all increased LH pulse amplitude whereas only naloxone increased GnRH pulse amplitude (P < 0.01). There was an interaction (P < 0.01) between steroid and naloxone on LH, but not GnRH, pulse amplitude. Both LD photoperiod and T increased both LH and GnRH (P < 0.01) interpulse-interval (IPI). Naloxone decreased GnRH IPI (P < 0.01). The LH/GnRH pulse amplitude ratio was (P < 0.02) increased by T--likely a secondary response to the T-induced increase in IPI. These results are interpreted as showing that in the ram the endogenous opiate peptides regulate both GnRH pulse frequency and amplitude, but that their specific role is modulated by photoperiod and T. These results do not support the concept that the opiate peptides are the primary mediators of the negative feedback effects of T.

Distribution of estrogen receptor-beta messenger ribonucleic acid in the male sheep hypothalamus.

As a first step in determining possible influences of the newly discovered estrogen receptor (ER)-beta on reproduction, we have localized mRNA for ER-beta within the male sheep hypothalamus using in situ hybridization and a rat ER-beta cRNA probe. Highest amounts of hybridization signal were observed in the preoptic area (POA), bed nucleus of the stria terminalis, paraventricular nucleus, and supraoptic nucleus. Relatively moderate amounts of hybridization signal were observed in the retrochiasmatic area (RCH), anterior hypothalamic area, dorsomedial hypothalamus, and lateral hypothalamus. Only a low level of hybridization signal was observed in the ventromedial hypothalamus, suprachiasmatic nucleus, and arcuate nucleus. The presence of ER-beta mRNA in several areas of the male sheep hypothalamus suggests multiple functions for this receptor. The distribution of ER-beta in the ovine hypothalamus was similar to that described for the rat, suggesting a high degree of functional conservation across species. A role for ER-beta in influencing reproduction is suggested by its presence in the POA and RCH, regions of the hypothalamus that control reproduction.

Regulation of gonadotrophin-releasing hormone secretion by testosterone in male sheep.

In males, including the ram, testosterone, acting via its primary metabolites oestradiol and dihydrotestosterone (DHT), suppresses circulating LH concentrations. This effect is due primarily, although not totally, to decreased frequency of gonadotrophin-releasing hormone (GnRH) pulses. The arcuate-ventromedial region (ARC-VMR) of the mediobasal hypothalamus and possibly the medial preoptic area (mPOA) are sites at which oestradiol acts to suppress GnRH, but the site of DHT action is not known. Given that native GnRH neurones appear to contain few or no oestrogen or androgen receptors, the effects of testosterone metabolites probably are exerted by modulating activity of inhibitory interneurone systems such as beta-endorphin, dopamine, and gamma-aminobutyric acid (GABA). Although beta-endorphin clearly inhibits GnRH secretion, the observation that testosterone treatment during a long-day photoperiod reduced proopiomelanocortin (POMC) mRNA in the arcuate nucleus while coincidentally suppressing GnRH release indicates that beta-endorphin does not mediate the inhibitory effect of testosterone on GnRH. Activation of GABAA receptors in either the mPOA or ARC-VMR suppressed LH, whereas activation of GABAB receptors in the ARC-VMR increased LH pulse amplitude. Therefore, it is suggested that GABA acts in both regions to regulate LH. Whereas testosterone affects GABA metabolism in the rat hypothalamus, its effect in the ram hypothalamus is yet to be determined. Testosterone treatment activated dopaminergic cells in the retrochiasmatic A15 area in the same animals in which it suppressed POMC mRNA in the arcuate nucleus. This dopaminergic system may partially mediate the negative feedback effect of testosterone in the ram analogous to its role in partially mediating the negative effect of oestrogen in the ewe. Future studies must concentrate on determining how these and other putative inhibitory neuronal systems interact and how they in turn are regulated by environmental factors such as photoperiod.