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Background While racial/ethnic survival disparities have been described in pediatric oncology, the impact of income has not been extensively explored. We analyzed how public insurance influences 5‐year overall survival (OS) in young patients with sarcomas. Methods The University of California San Francisco Cancer Registry was used to identify patients aged 0‐39 diagnosed with bone or soft tissue sarcomas between 2000 and 2015. Low‐income patients were defined as those with no insurance or Medicaid, a means‐tested form of public insurance. Survival curves were computed using the Kaplan‐Meier method and compared using log‐rank tests and Cox models. Causal mediation was used to assess whether the association between public insurance and mortality is mediated by metastatic disease. Results Of 1106 patients, 39% patients were classified as low‐income. Low‐income patients were more likely to be racial/ethnic minorities and to present with metastatic disease (OR 1.96, 95% CI 1.35‐2.86). Low‐income patients had significantly worse OS (61% vs 71%). Age at diagnosis and extent of disease at diagnosis were also independent predictors of OS. When stratified by extent of disease, low‐income patients consistently had significantly worse OS (localized: 78% vs 84%, regional: 64% vs 73%, metastatic: 23% vs 30%, respectively). Mediation analysis indicated that metastatic disease at diagnosis mediated 15% of the effect of public insurance on OS. Conclusions Low‐income patients with bone and soft tissue sarcomas had decreased OS regardless of disease stage at presentation. The mechanism by which insurance status impacts survival requires additional investigation, but may be through reduced access to care., Low‐income patients with bone and soft tissue sarcomas had decreased overall survival compared to patients with private insurance regardless of disease stage at presentation. This survival disparity is partially mediated by presentation with advanced disease.

Study Objectives To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23–78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug–placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Mean drug–placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated. Clinical Trial Registration clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

STUDY OBJECTIVES: Our aim was to evaluate the effect of lemborexant versus zolpidem tartrate extended release 6.25 mg (ZOL) or placebo (PBO) on postural stability, auditory awakening threshold (AAT), and cognitive performance (cognitive performance assessment battery [CPAB]). METHODS: Healthy women (≥ 55 years) and men (≥ 65 years) were randomized, double-blind, to 1 of 4-period, single-dose crossover sequences, starting with lemborexant 5 mg (LEM5), 10 mg (LEM10), ZOL, or PBO. A ≥ 14-day washout followed all 4 treatments. Assessments were middle-of-the-night (MOTN) change from baseline in postural stability (primary prespecified comparison: LEM vs ZOL), AAT, absolute AAT, and CPAB for LEM5 and LEM10 versus ZOL and PBO; and morning change from baseline in postural stability and CPAB for LEM5 and LEM10 versus ZOL and PBO. Change from baseline measures were time-matched to a baseline night/morning when no study drug was administered. RESULTS: MOTN: Mean MOTN change from baseline in body sway was significantly higher for ZOL versus both lemborexant doses. There were no differences among the treatments regarding decibels required to awaken a participant. LEM5 was not statistically different from PBO on any CPAB domain; LEM10 and ZOL showed poorer performance on some tests of attention and/or memory. Morning: Body sway and cognitive performance following LEM5 or LEM10 did not differ from PBO; body sway was significantly higher for ZOL than PBO. Rates of treatment-emergent adverse events were low; there were no serious adverse events. CONCLUSIONS: Lemborexant causes less postural instability than a commonly used sedative-hypnotic and does not impair the ability to awaken to auditory signals. CLINICAL TRIALS REGISTRATION: Registry: ClinicalTrials.gov; Name: Crossover Study to Evaluate the Effect of Lemborexant Versus Placebo and Zolpidem on Postural Stability, Auditory Awakening Threshold, and Cognitive Performance in Healthy Subjects 55 Years and Older; URL: https://clinicaltrials.gov/ct2/show/NCT03008447; Identifier: NCT03008447. CITATION: Murphy P, Kumar D, Zammit G, Rosenberg R, Moline M. Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening. J Clin Sleep Med. 2020;16(5):765–773.

To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment.Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs).A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (∼63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ≥ 5 mg (Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838; Identifier: NCT01995838.

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.

Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39.

Objectives: Intravenous ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. Methods: A comparison was made between routinely collected symptom measures 1–2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6–19 years. Results: Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. Conclusions: Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted. & 2012 Elsevier B.V. All rights reserved.

Existential distress is of clinical concern in patients with terminal illness. Although existential distress has been used to describe a broad spectrum of psychological disturbances, its narrower definition may be confined to distress that arises when the meaning and value of one's life is unclear, and is comorbid with feelings of loneliness and low self-worth. To promote further study, we developed and pilot-tested a 10-item Existential Distress Scale (EDS). Twenty-one patients with advanced cancer were recruited from a palliative care unit. Measures of existential distress, death anxiety, depression, performance status and physical symptom burden were collected. The EDS showed promising psychometric properties, including significant associations with death anxiety and depression. Thirty-eight per cent of the sample reported great or unbearable distress on at least one existential concern. The EDS may be administered to measure existential distress in patients with advanced cancer and clinicians may find the instrument useful to initiate a structured discussion about this symptom.

Both hypoxia and carbon dioxide increase cerebral blood flow (CBF), and their effective interaction is currently thought to be additive. Our objective was to test this hypothesis. Eight healthy subjects breathed a series of progressively hypoxic gases at three levels of carbon dioxide. Middle cerebral artery velocity, as an index of CBF; partial pressures of carbon dioxide and oxygen and concentration of oxygen in arterial blood; and mean arterial blood pressure were monitored. The product of middle cerebral artery velocity and arterial concentration of oxygen was used as an index of cerebral oxygen delivery. Two-way repeated measures analyses of variance (rmANOVA) found a significant interaction of carbon dioxide and hypoxia factors for both CBF and cerebral oxygen delivery. Regression models using sigmoidal dependence on carbon dioxide and a rectangular hyperbolic dependence on hypoxia were fitted to the data to illustrate this interaction. We concluded that carbon dioxide and hypoxia act synergistically in their control of CBF so that the delivery of oxygen to the brain is enhanced during hypoxic hypercapnia and, although reduced during normoxic hypocapnia, can be restored to normal levels with progressive hypoxia.

ObjectiveTo determine differences in patient characteristics, antiretroviral therapy (ART) regimen characteristics, and regimen refill adherence for human immunodeficiency virus (HIV)-focused pharmacy (HIV-P) versus traditional pharmacy (TP) users.DesignRetrospective cohort study.SettingCalifornia Walgreens pharmacies from May 2007 to August 2009.ParticipantsHIV-positive patients with greater than 30 days of antiretroviral prescription claims.InterventionDeidentified prescription records for patients filling any ART prescription at any California Walgreens pharmacy during the study period were assessed.Main outcome measuresART regimen refill adherence (calculated by modified medication possession ratio [mMPR]) and dichotomous measure of optimal adherence of 95% or greater.Results4,254 HIV-P and 11,679 TP users were included. Compared with TP users, HIV-P users traveled farther to pharmacies (5.03 vs. 1.26 miles, P < 0.01). A greater proportion of HIV-P users filled prescriptions for chronic diseases (35% vs. 30%) and received fixed-dose combination antiretroviral tablets (92% vs. 83%) (all P < 0.01). Median mMPR was higher for HIV-P users (90% vs. 77%, P < 0.0001). After adjusting for age, gender, insurance, medication use, and distance from pharmacy, use of HIV-P (odds ratio 1.90 [95% CI 1.72-2.08]) and fixed-dose combination antiretroviral tablets (3.34 [2.84-3.96]) were most strongly associated with having 95% or greater ART regimen refill adherence.ConclusionFor HIV-positive patients struggling with antiretroviral adherence, clinicians may consider minimizing pill burden with combination tablets and referral to an HIV-focused pharmacy.

Background: Because of the renal elimination and increased risk for bleeding events at supratherapeutic doses of eptifibatide, the manufacturer recommends dosing adjustment in patients with renal dysfunction. Methods commonly used to estimate renal dysfunction in hospital settings may be inconsistent with those studied and recommended by the manufacturer Objective: To compare hypothetical renal dosing adjustments of eptifibatide using both the recommended method and several other commonly used formulas for estimating kidney function. Methods: Sex, age, weight, height, serum creatinine, and estimated glomerular filtration rate (eGFR) were obtained retrospectively from the records of patients who received eptifibatide during a 12-month period. Renal dosing decisions were determined for each patient based on creatinine clearance (CrCI) estimates via the Cockcroft-Gault formula (CG) with actual body weight (ABW), ideal body weight (IBW) or adjusted weight (ADJW), and eGFR from the Modification of Diet in Renal Disease formula. Percent agreement and Cohen κ were calculated comparing dosing decisions for each formula to the standard CG-ABW. Results: In this analysis of 179 patients, percent agreement as compared to CG-ABW varied (CG-IBW: 90.50%, CG-ADJW: 95.53%, and eGFR: 93.30%). All κ coefficients were categorized as good. In the 20% of patients receiving an adjusted dose by any of the methods, 68.6% could have received a dose different from that determined using the CG-ABW formula. Conclusions: In the patients with renal impairment (CrCI

This study evaluated adherence to medications used to treat chronic conditions for patients with 90-day prescriptions, comparing patients with access to workplace pharmacy services versus patients using mail order services. De-identified pharmacy claims data were used to compute medication possession ratio and gaps in therapy. Results were compared for patients who filled 90-day prescriptions at workplace pharmacies versus patients who filled 90-day prescriptions using mail order pharmacy services in a 1-year period. Statistical tests to assess between group differences were performed controlling for differences because of age, sex, number of select chronic conditions, number of unique medication therapeutic classes, and patient out-of-pocket cost per therapy day. Statistically significant differences were found between patients who filled their maintenance medications at the worksite compared to those who used mail-order pharmacy services. Patients filling prescriptions at a workplace pharmacy were 22% less likely to have a gap in therapy of over 30 days compared to similar patients using mail order services. Workplace pharmacy utilizers also had overall adherence rates 3.68% higher than patients who utilized mail order pharmacy services. Our analysis suggests that it may not be just the quantity of medication dispensed that impacts patients' adherence to their prescription medication, but a variety of other factors including pharmacist-patient interaction. Having a pharmacist on-site and available to patients with chronic considerations could provide added value. These results can aid employers and other stakeholders to decide which prescription benefits to offer their employees and members.

We examined administrative outcomes after opening an oncology acute palliative care unit (APCU), to determine attainment of administrative targets related to the unit's function of acute palliation.We retrospectively reviewed the administrative database for our APCU for the 5 years following its opening in 2003. Data were abstracted on demographic information, as well as source of admission, primary reason for admission, discharge destination, inpatient death rate, and length of stay. Linear regression and the Cochran-Armitage trend test were used for analysis. In keeping with targets set at the unit's opening, our primary hypotheses were that outpatient admissions, admissions for symptom control, and discharges home would increase over the study period; secondary hypotheses were that length of stay and inpatient death rate would decrease.There were 1748 admissions during the study period: the median age was 64, 54% were women, and the most common cancer sites were gastrointestinal (24%), lung (20%), and gynecologic (13%). There were significant changes for all primary endpoints: outpatient admissions increased from 47% to 70% (p0.0001), admissions for symptom control increased from 42% to 75% (p0.0001), and discharges home increased from 18% to 39% (p0.0001). The secondary end points of death rate and length of stay decreased from 65% to 40% (p0.0001) and 12 to 11 days (p = 0.54), respectively.Setting and adhering to administrative targets for an APCU is possible with appropriate admission criteria, adequate community resources, and education of patients, families and health professionals regarding the model of care.

Atypical absence seizures (AASs) represent a pediatric malignant seizure type that commonly exists as a component of Lennox-Gastaut syndrome. AAS involves both the hippocampal and thalamocortical circuitry in slow spike-and-wave discharges (SSWD) and is associated with cognitive dysfunction. The electrographic, behavioral, and pharmacological features of clinical AAS have been reproduced in rats chronically in the AY-9944 (AY) model. AY rats show spontaneous SSWD involving the hippocampus, a structure that is highly implicated in learning and memory. The purpose of the present study was to determine whether AY rats exhibit cognitive deficits that mirror those observed in AAS clinically. Hippocampal function was examined in AY animals both in vitro with electrophysiology (i.e., synaptic plasticity) and in vivo with a hippocampus-dependent radial arm maze (RAM) task that is designed to assess spatial cognition. In vitro tests of synaptic plasticity revealed impairments in long-term potentiation (LTP), paired-pulse facilitation (PPF), and presynaptic depression (PD). Consistently, performance of AY animals in RAM revealed fewer perfect entries, a greater number of errors, and required more training days to learn the task than saline-treated controls. The abolishment of spontaneous seizures by ethosuximide failed to recover the perturbed spatial learning and working memory in AY animals. AY rats demonstrate altered hippocampal functioning as manifested by altered synaptic plasticity and cognition. The relationship between AAS and cognitive deficit remains uncertain and the pathophysiology of both in AY treated requires further investigation.

To evaluate the combination of rectal indomethacin with patient controlled intravenous morphine analgesia (PCA) on postoperative pain relief and opioid use after cardiac surgery.With institutional ethics approval, 57 consenting adults undergoing elective aortocoronary bypass surgery were randomly assigned preoperatively in a double-blind fashion to receive either placebo (n = 26) or indomethacin 100 mg suppositories (n = 31), 2-3 hr postoperatively, and 12 hr later. Both groups utilized PCA morphine. Pain scores in the two treatment groups were assessed on a 10-cm visual analogue scale (VAS) (at rest and with cough) at 4, 6, 12, 18 and 24 hr after initial dosing, and were analyzed through a 2 x 5 repeated measures of variance. The 24 hr analgesic consumption, 12 and 24 hr chest tube blood loss, and time to tracheal extubation were also recorded, and compared for the two treatment arms through Student's t test on independent samples.Postoperative morphine consumption in the first 24 hr was 38% less in the indomethacin group (22.40 +/- 12.55 mg) than the placebo group (35.99 +/- 25.84 mg), P = 0.019. Pain scores, measured with a VAS, were 26% to 66% lower in the indomethacin vs placebo group at rest (P = 0.006), but not with cough, for all times assessed. There was no difference in blood loss (at 12 hr) or time to tracheal extubation for both groups.The combination of indomethacin with morphine after cardiac surgery results in reduced postoperative pain scores and opioid use without an increase in side effects.

This study measures waiting times and consultation times at convenient care clinics (CCCs), and compares them with equivalent times in traditional, family practice, physician offices. The analysis was limited to conditions most commonly treated at CCCs. It was found that patients using CCCs had significantly shorter waiting times from check-in to seeing a clinician than the equivalent waiting times reported by patients at family practice physicians’ offices and that CCC patients had significantly longer consultation times with the clinician than those reported by family practice patients. Applying a correction factor to adjust for potential differences between real waiting times and perceived waiting times did not substantially alter the conclusions. Shorter waiting times may increase satisfaction and thereby encourage patients to seek care; and spending additional time with the clinician may help ensure that all of a patient’s concerns or questions are addressed. This study provides objective evidence from a large database that CCCs provide prompt, satisfying care.

Patient adherence (the degree to which patients follow their therapeutic regimen as prescribed within a set period of time) and persistence (the time to treatment discontinuation, with a permissible gap) with drug therapy are essential components of HIV/AIDS treatment. Select community pharmacies offer specialized services for HIV/AIDS patients to help combat some of the barriers to adherence and persistence. We assessed adherence and persistence with antiretroviral therapy (ART) for patients using HIV-specialized pharmacies in nine cities from seven states compared to traditional community pharmacy users over a 1-year period. Data were limited to one pharmacy chain. Propensity scoring was used to obtain 1:1 matches for "Specialized" and "Traditional" pharmacy users based on age, gender, number of prescription-inferred chronic conditions (obtained by mapping a patient's prescriptions to the Medi-Span Drug Indications Database), and presence of prescription anxiety and/or depression medication, resulting in 7064 patients in each group. Proportion of days covered (PDC) was used to measure adherence. Specialized pharmacy users had a significantly greater mean (74.1% versus 69.2%, p

Background Screening efforts using the Papanicolaou test have significantly reduced the incidence of cervical cancer in countries with an active screening program. However, this test does not accurately identify all abnormal cases. Significant effort has been expended investigating molecular markers that could improve the sensitivity and specificity of detection of high-grade disease. In this study, we describe the selection and characterization of a set of antibodies to the minichromosome maintenance proteins MCM6 and MCM7 that highlight cervical disease in an immunoassay. Methods Antibodies to MCM6 or MCM7 proteins were identified from hybridoma clones screened against tissue microarrays containing different grades of diseased cervical tissue along with normal controls. We determined epitopes by western blotting against nested truncations of either the MCM6 or MCM7 proteins fused to GFP protein. We also determined specificity by western blotting against a panel of major MCM proteins (MCM2-MCM8). Affinity to recombinant antigen and epitope-only peptides was determined using solution-phase binding and determination of free antibody concentration by ELISA. Optimization studies resulted in the selection of antibodies specific to MCM6 and MCM7 for use in immunocytochemistry (ICC) with cervical cytology samples. Results Four antibodies were identified that demonstrated strong nuclear staining of abnormal cervical epithelial cells in immunohistochemistry (IHC) of cervical biopsies with minimal background staining of normal cervical tissues. Of these four antibody clones, 2E6.7 (MCM7) and 9D4.3 (MCM6) were chosen for further study. Linear epitopes of at most 12 amino acids were identified and verified by binding to epitope-only peptides. Affinities of at least 4 × 10 − 9 M were determined for these two antibodies and both were found to be specific for their respective antigens by western blotting. Clones 9D4.3 and 2E6.7 were also determined to stain abnormal cells in high-grade squamous intraepithelial lesion cytology samples, with minimal background staining of normal cells. Conclusion In this study, we present a method for selecting antibodies that perform well in IHC and ICC applications and characterize two antibodies generated by this method that effectively stain abnormal cells in cervical cancer tissue and cervical cytology samples.

The heat-shock response (HSR), a highly conserved cellular response, is characterized by rapid expression of heat-shock proteins (HSPs), and inhibition of other synthetic activities. The HSR can attenuate inflammatory responses, via suppression of transcription factor activation. A HSR can be induced pharmacologically by HSP90 inhibitors, through activation of the transcription factor Heat Shock Factor 1 (HSF1). In the present study we characterized the effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic derivative of the naturally occurring HSP90 inhibitor geldanamycin, on glial inflammatory responses and the development of experimental autoimmune encephalomyelitis. In primary enriched glial cultures, 17-AAG dose dependently reduced lipopolysaccharide-dependent expression and activity of inducible nitric oxide synthase, attenuated interleukin (IL)-1beta expression and release, increased inhibitor of kappaB protein levels, and induced HSP70 expression. 17-AAG administration to mice immunized with myelin oligodendrocyte glycoprotein peptide prevented disease onset when given at an early time, and reduced clinical symptoms when given during ongoing disease. T cells from treated mice showed a reduced response to immunogen re-stimulation, and 17-AAG reduced CD3- and CD28-dependent IL-2 production. Together, these data suggest that HSP90 inhibitors could represent a new approach for therapeutic intervention in autoimmune diseases such as multiple sclerosis.

Studies have proposed that the features of diabetes clinics may decrease hospital utilization and costs by reducing complications and providing more efficient outpatient care. We compared the health care utilization associated with a diabetes center (DC) and a general medicine clinic (GMC).Retrospective cohort study.An urban academic medical center.Type 2 diabetes patients (N = 601) under care in a DC and GMC before March 1996.We compared baseline patient characteristics and outpatient care for the period of March 1996 to August 1997. Using administrative data from March 1996 to October 2000, we compared the probability of a hospitalization, length of stay, costs of hospitalizations, the probability of an emergency room visit, and costs of emergency room visits. Diabetes center patients had a longer mean duration of diabetes (12 years vs 6 years, P.01), more baseline microvascular disease (65% vs 44%, P.01), and higher baseline glucose levels (hemoglobin A1c 8.6% vs 7.9%, P.01) than GMC patients. Diabetes center patients received more intensive outpatient care directed toward glucose monitoring and control. In all crude and adjusted analyses of hospitalizations and emergency room visits, we found no statistically significant differences for inpatient utilization or cost outcomes comparing clinic populations.Diabetes center attendance did not have a definitive positive or negative impact on inpatient resource utilization over a 4-year period. However, DC patients had more severe diabetes but no greater hospital utilization compared with GMC patients. Clear demonstration of the clinical and financial benefits of features of diabetes centers will require long-term controlled trials of interventions that promote comprehensive diabetes care, including cardiovascular prevention.

To test effects of a web-based decision support tool, the diabetes Disease Management Application (DMA), developed to improve evidence-based management of type 2 diabetes.We conducted a group randomized controlled trial of 12 intervention and 14 control staff providers and 307 intervention and 291 control patients with type 2 diabetes in a hospital-based internal medicine clinic. Providers were randomly assigned from May 1998 through April 1999 to have access to the DMA (intervention) or not to have access (control). The DMA displays interactive patient-specific clinical data, treatment advice, and links to other web-based care resources. We compared patients in the intervention and control groups for changes in processes and outcomes of care from the year preceding the study through the year of the study by intention-to-treat analysis.The DMA was used for 42% of scheduled patient visits. The number of HbA(1c) tests obtained per year increased significantly in the intervention group (+0.3 tests/year) compared with the control group (-0.04 tests/year, P = 0.008), as did the number of LDL cholesterol tests (intervention, +0.2 tests/year; control, +0.01 tests/year; P = 0.02) and the proportions of patients undergoing at least one foot examination per year (intervention, +9.8%; control, -0.7%; P = 0.003). Levels of HbA(1c) decreased by 0.2 in the intervention group and increased by 0.1 in the control group (P = 0.09); proportions of patients with LDL cholesterol levels130 mg/dl increased by 20.3% in the intervention group and 10.5% in the control group (P = 0.5).Web-based patient-specific decision support has the potential to improve evidence-based parameters of diabetes care.

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. We compared hyperglycemia management with the management of the cardiovascular disease risk factors hypertension and hypercholesterolemia in a cohort of type 2 diabetes patients.We randomly selected 601 patients with type 2 diabetes seen at the outpatient practices of an academic medical center and assessed the care they received during an 18-month period. We compared proportions of patients who had hemoglobin A(1c) (HbA(1c)) levels, blood pressure, or total cholesterol levels measured; who had been prescribed any drug therapy if HbA(1c) levels, systolic blood pressure, or low-density lipoprotein (LDL) cholesterol levels exceeded recommended treatment goals; and who had been prescribed greater-than-starting-dose therapy if these values were above those of treatment goals.Patients were less likely to have cholesterol levels (76%, n = 455) measured than HbA(1c) (92%, n = 552) levels or blood pressure (99%, n = 595; P0.0001 for either comparison). The proportion of patients that received any drug therapy was greater for above-goal HbA(1c) (92%, n = 348) than for above-goal systolic blood pressure (78%, n = 274) or LDL cholesterol (38%, n = 82; P0.0001 for each comparison). Similarly, patients whose HbA(1c) levels were above the treatment goal (80%, n = 302) were more likely to receive greater-than-starting-dose therapy, compared with those who had above-goal systolic blood pressure (62%, n = 218) and LDL cholesterol levels (13%, n = 28; P0.0001).In this cohort, hypercholesterolemia and hypertension were managed less aggressively than was hyperglycemia. Given the prevalence of cardiovascular disease in patients with type 2 diabetes, increased screening for hypercholesterolemia and more aggressive drug therapy for hypercholesterolemia and hypertension are needed.

The purpose of this research was to determine if adults can provide a true rating of their own childhood and current symptoms of attention deficit hyperactivity disorder (ADHD).The authors conducted two studies. In study 1, 50 adult subjects completed a questionnaire assessing their ADHD symptoms in childhood. In addition, a parent of each subject completed a questionnaire rating the subject's childhood ADHD symptoms. In study 2, 100 adult subjects completed a questionnaire rating their own current ADHD symptoms. The subject's partner also completed a questionnaire rating the subject's current ADHD symptoms. The correlation between subject and observer ratings was measured in each study. Inattentive symptoms, hyperactive-impulsive symptoms, and total symptoms were analyzed.Good correlations were found between subject and observer scores in both studies.The diagnosis of ADHD in adults relies on an accurate recall of childhood behavior and an accurate account of current behavior. The results of this study suggest that adults can give a true account of their childhood and current symptoms of ADHD.

Objective To provide a growth reference standard for children with quadriplegic cerebral palsy (QCP). Growth references specific to children with cerebral palsy would facilitate uniformity in clinical appraisal of their growth and nutritional status and would simplify comparative interpretation of growth data. Design Weights and lengths were obtained according to standardized procedures. Measurements were taken at time of visit to an orthopedic clinic and from retrospective review of charts. Subjects Three hundred sixty children with QCP. Growth data were based on 1,630 observations. Analysis Growth curves representing the 10th, 50th, and 90th percentiles were estimated using a smoothing splines technique. Statistical bootstrapping was performed to confirm significant differences from the growth charts of the National Center for Health Statistics (NCHS). Results Growth charts were constructed for boys and girls, aged 0 to 120 months, depicting length for age, weight for age, and weight for length. Average differences in length for age, weight for age, and weight for length between children with QCP and NCHS standards were −2.3 z , −2.4 z , −1.3 z for boys, and −2.1 z , −2.1 z , −1.1 z for girls. Children with QCP fell progressively behind in stature and weight. Compared with their NCHS counterparts, they were 5% shorter at 2 years of age and more than 10% shorter at 8 years of age. Application Charts representing the pattern of growth in children with QCP should be accessible to parents and health care professionals to facilitate evaluation and monitoring of nutritional status. J Am Diet Assoc. 1996; 96:680-685 .

Several studies have demonstrated that schizophrenia patients can improve their performance on the Wisconsin Card Sorting Test if given appropriate training. However, it is not clear if they are learning a generalizable problem-solving strategy rather than a circumscribed rule. We examined this question by training patients on one of two related problem-solving tests and assessing transfer of training effects across the two instruments; a third group received practice on both tests, but no training. Subjects were 27 schizophrenia patients in the latter stages of an acute hospital admission. While subjects in both training conditions exhibited marked improvement on the trained test, the results failed to reveal any evidence of generalization. Subjects trained on one test performed no better on the other instrument than subjects who received practice only. These results suggest that gains in WCST performance reported in the literature after brief training or instructions may not reflect any meaningful changes in problem solving capacity or in any underlying neurological function. Implications of the findings for rehabilitation programs are discussed, along with limitations of the data and recommendations for future research.

ContextIncreased risk for cardiovascular disease in persons with glucose intolerance (impaired glucose tolerance and type 2 diabetes mellitus) is not fully explained by concomitant elevations in traditional atherosclerosis risk factors. Hyperinsulinemia associated with glucose intolerance may increase risk directly, or its effect could be mediated through impaired hemostatic function.ObjectiveTo evaluate associations between fasting insulin levels and hemostatic factors in subjects with normal and impaired glucose homeostasis.DesignCross-sectional analysis conducted between January 1991 and June 1995.SettingThe population-based Framingham Offspring Study.SubjectsA total of 1331 men and 1631 women aged 26 to 82 years, without diagnosed diabetes or cardiovascular disease and classified as having normal glucose tolerance (80.2%) or glucose intolerance (impaired glucose tolerance and impaired fasting glucose combined, 15.2%; previously undiagnosed diabetes, 4.7%) using an oral glucose tolerance test.Main Outcome MeasuresTrends across quintiles of fasting insulin in levels of plasminogen activator inhibitor 1 (PAI-1) antigen, tissue-type plasminogen activator (tPA) antigen, von Willebrand factor (vWF) antigen, factor VII antigen, fibrinogen, and plasma viscosity. We stratified analyses by sex and glucose tolerance status and adjusted hemostatic factor levels for obesity, lipid levels, and traditional cardiovascular disease risk factors.ResultsMean levels of all hemostatic factors (except for fibrinogen in men) increased across fasting insulin quintiles among subjects with normal glucose tolerance (P

ObjectiveDivision of secondary chords (chordal cutting) has been proposed as a method for decreasing mitral valve leaflet tethering and mitral regurgitation in patients with ischemic mitral regurgitation. However, very little clinical data exist to date for this procedure.MethodsWe compared echocardiographic and clinical data in patients who underwent chordal-cutting mitral valve repair (n = 43) and those undergoing conventional mitral valve repair (control, n = 49) for ischemic mitral regurgitation.ResultsPatients who underwent chordal cutting had a higher prevalence of recent myocardial infarction, left main disease, diabetes, and peripheral vascular disease (all P < .05). Left ventricular ejection fraction was lower in the chordal-cutting group (33 ± 2% vs 44 ± 2%) (mean ± SE) and preoperative tent height was greater (11.7 ± 0.5 vs 9.7 ± 0.6 mm; both P < .01). In-hospital mortality was 10% in control patients and 9% in the chordal-cutting group (P = .9). Other complication rates were similar for the two groups. The reduction in tent height before-to-after repair was similar in the two groups of patients, but those undergoing chordal cutting had a greater reductions in tent area (53 ± 3% vs 41 ± 3%; P = .01). The chordal-cutting group also had greater mobility of the anterior leaflet, as measured by a reduction in the distance between the free edge of the anterior mitral valve leaflet and the posterior left ventricular wall (24 ± 3% vs 11 ± 4%; P = .01). Control patients had more recurrent mitral regurgitation during 2 years of follow-up by univariate (37% vs 15%; P = .03) and multivariate analysis (P = .03). Chordal cutting did not adversely affect postoperative left ventricular ejection fraction (10% ± 5% relative increase in left ventricular ejection fraction vs 11% ± 6% in the control group; P = .9).ConclusionChordal cutting improves mitral valve leaflet mobility and reduces mitral regurgitation recurrence in patients with ischemic mitral regurgitation, without any obvious deleterious effects on left ventricular function.