Bypassing nearest hospital for more distant neuroscience care in head-injured adults with suspected traumatic brain injury: findings of the head injury transportation straight to neurosurgery (HITS-NS) pilot cluster randomised trial

OBJECTIVE: Reconfiguration of trauma services, with direct transport of patients with traumatic brain injury (TBI) to specialist neuroscience centres (SNCs)-bypassing non-specialist acute hospitals (NSAHs), could improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) may worsen outcomes when compared with selective secondary transfer from nearest NSAH to SNC. We conducted a pilot cluster randomised controlled trial to determine the feasibility and plausibility of bypassing suspected patients with TBI -directly into SNCs-producing a measurable effect. SETTING: Two English Ambulance Services. PARTICIPANTS: 74 clusters (ambulance stations) were randomised within pairs after matching for important characteristics. Clusters enrolled head-injured adults-injured nearest to an NSAH-with internationally accepted TBI risk factors and stable ABC. We excluded participants attended by Helicopter Emergency Medical Services or who were injured more than 1 hour by road from nearest SNC. INTERVENTIONS: Intervention cluster participants were transported directly to an SNC bypassing nearest NSAH; control cluster participants were transported to nearest NSAH with selective secondary transfer to SNC. OUTCOMES: Trial recruitment rate (target n=700 per annum) and percentage with TBI on CT scan (target 80%) were the primary feasibility outcomes. 30-day mortality, 6-month Extended Glasgow Outcome Scale and quality of life were secondary outcomes. RESULTS: 56 ambulance station clusters recruited 293 patients in 12 months. The trial arms were similar in terms of age, conscious level and injury severity. Less than 25% of recruited patients had TBI on CT (n=70) with 7% (n=20) requiring neurosurgery. Complete case analysis showed similar 30-day mortality in the two trial arms (control=8.8 (2.7-14.0)% vs intervention=9.4(2.3-14.0)%). CONCLUSION: Bypassing patients with suspected TBI to SNCs gives an overtriage (false positive) ratio of 13:1 for neurosurgical intervention and 4:1 for TBI. A measurable effect from a full trial of early neuroscience care following bypass is therefore unlikely. TRIAL REGISTRATION NUMBER: ISRCTN68087745

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial

The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate “activity” stages (I-III) where the outcome measure is failure-free survival (FFS) and one final “efficacy” stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims

A retrospective study on the impact of comorbid depression or anxiety on healthcare resource use and costs among diabetic neuropathy patients

<p>Abstract</p> <p>Background</p> <p>Diabetic neuropathy (DN) is a common complication of diabetes that has significant economic burden, especially for patients with comorbid depression or anxiety. This study examines and quantifies factors associated with healthcare costs among patients diagnosed with diabetic neuropathy (DN) with or without a comorbid diagnosis of depression or anxiety (DA) using retrospective administrative claims data. No study has examined the differences in economic outcomes depending on the presence of comorbid DA disorders.</p> <p>Methods</p> <p>Over-age-18 individuals with 1+ diagnosis of DN in 2005 were selected. The first observed DN claim was considered the "index date." All individuals had a 12-month pre-index and follow-up period. For both under-age-65 commercially insured and over-age-65 individuals with employer-sponsored Medicare supplemental insurance, we constructed 2 subgroups for individuals with DA (DN-DA) or without (DN-only). Patients' clinical characteristics over pre-index period were compared. Multivariate regressions were performed to assess whether DN-DA patients had higher utilization of healthcare resources and costs than DN-only patients, controlling for demographic and clinical characteristics.</p> <p>Results</p> <p>We identified 16,831 DN-only and 1,699 DN-DA patients in the Medicare supplemental cohort, as well as 17,205 and 3,105 in the commercially insured. DN-DA patients had higher prevalence of diabetes-related comorbidities for cardiovascular disease, cerebrovascular/peripheral vascular disease, nephropathy, obesity, and hypoglycemic events than DN-only patients (all p < 0.05). Controlling for differences in demographic and clinical characteristics, DN-DA patients had $9,235 (p < 0.05) higher total healthcare costs than patients with DN-only among those with Medicare supplemental coverage ($26,718 vs. $17,483), and$10,389 (p < 0.05) more total costs among commercially insured ($29,775 vs.$19,386). Factors associated with increased costs included insurance type, geographical region, diabetes-related comorbidities, and insulin therapy.</p> <p>Conclusion</p> <p>These findings indicate that the healthcare costs were significantly higher for DN patients with depression or anxiety relative to those without such comorbid disorders.</p

Limits on Gravitational-Wave Emission from Selected Pulsars Using LIGO Data

We place direct upper limits on the amplitude of gravitational waves from 28 isolated radio pulsars by a coherent multidetector analysis of the data collected during the second science run of the LIGO interferometric detectors. These are the first direct upper limits for 26 of the 28 pulsars. We use coordinated radio observations for the first time to build radio-guided phase templates for the expected gravitational-wave signals. The unprecedented sensitivity of the detectors allows us to set strain upper limits as low as a few times 10^(-24). These strain limits translate into limits on the equatorial ellipticities of the pulsars, which are smaller than 10^(-5) for the four closest pulsars

Sexual dimorphism in trait variability and its eco-evolutionary and statistical implications

Biomedical and clinical sciences are experiencing a renewed interest in the fact that males and females differ in many anatomic, physiological, and behavioral traits. Sex differences in trait variability, however, are yet to receive similar recognition. In medical science, mammalian females are assumed to have higher trait variability due to estrous cycles (the 'estrus-mediated variability hypothesis'); historically in biomedical research, females have been excluded for this reason. Contrastingly, evolutionary theory and associated data support the 'greater male variability hypothesis'. Here, we test these competing hypotheses in 218 traits measured in >26,900 mice, using meta-analysis methods. Neither hypothesis could universally explain patterns in trait variability. Sex-bias in variability was trait-dependent. While greater male variability was found in morphological traits, females were much more variable in immunological traits. Sex-specific variability has eco-evolutionary ramifications including sex-dependent responses to climate change, as well as statistical implications including power analysis considering sex difference in variance

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14–41%); the intent-to-treat response rate was 21% (CI 95%: 12–34%). Median time to neurologic progression was 49 days (range 1–515(+)); median survival was 88 days (range 1–515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians. © 2001 Cancer Research Campaign http://www.bjcancer.co

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure. © 2014 European Association of Urology

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Searching for gravitational waves from known pulsars

We present upper limits on the amplitude of gravitational waves from 28 isolated pulsars using data from the second science run of LIGO. The results are also expressed as a constraint on the pulsars' equatorial ellipticities. We discuss a new way of presenting such ellipticity upper limits that takes account of the uncertainties of the pulsar moment of inertia. We also extend our previous method to search for known pulsars in binary systems, of which there are about 80 in the sensitive frequency range of LIGO and GEO 600.Comment: Accepted by CQG for the proceeding of GWDAW9, 7 pages, 2 figure

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi