Epilepsy and antiseizure medications increase all-cause mortality in dialysis patients in the United States.

Seizures have been associated with uremia, but there are few data regarding the prevalence, treatment, and outcomes of patients with end-stage renal disease (ESRD) with epilepsy compared to those with ESRD without epilepsy. Here we conducted a retrospective cohort study using the United States Renal Data System to assess mortality and antiseizure medication prescriptions among patients with ESRD with and without a diagnosis of epilepsy. A modified Poisson regression with a robust variance was used to estimate the association between epilepsy status and mortality, and evaluate effect modification by neurology consultation. Additionally antiseizure medications were assessed in relation to mortality among those with epilepsy. Of 148,294 patients with ESRD in the cohort, 13,094 (8.8%) met a claims-based definition for epilepsy. Among those with epilepsy, 80.9% filled an anticonvulsant or hydantoin prescription in 2013-2014, compared to 33.3% without epilepsy. After adjustment for confounders, the mortality risk among those with epilepsy was 1.11 (95% confidence interval: 1.07, 1.14) times higher than those without. An epilepsy diagnosis was associated with a 15% increase in mortality risk among patients who did not have a neurology consultation (relative risk: 1.15 [95% confidence interval: 1.10, 1.20]), but this risk was attenuated among patients with a neurology consultation (1.07 [1.03, 1.11]). Prescription of gabapentin to patients with an epilepsy diagnosis compared to other antiseizure medications was associated with increased mortality (1.08 [1.01, 1.15]). Thus, patients with ESRD treated with dialysis have a high prevalence of epilepsy, which was associated with increased mortality risk compared to those without epilepsy. Hence, appropriate multidisciplinary care, treatment, and medication selection may reduce mortality among dialysis patients with epilepsy.

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aß Reduction without Cardiovascular Liabilities.

BACE1 inhibition to prevent Aß peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aß levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious ß-secretase inhibitors for the potential treatment of Alzheimer's disease.

The ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aß levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis.

Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 µM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aß levels in cerebrospinal fluid (CSF).

Preaccession fitness and body composition as predictors of attrition in U.S. Army recruits.

The Assessment of Recruit Motivation and Strength (ARMS) project evaluated whether active duty Army enlistees who exceeded weight and body-fat standards but were able to pass the ARMS physical fitness test were at elevated risk of early attrition relative to the traditional recruit population. Attrition among 1146 overweight and overbody-fat (OBF) recruits who passed ARMS was compared to 10,514 fully qualified (FQ) recruits who began service in February 2005 through September 2006. The ARMS test includes a 5-minute step test and a 1-minute pushup test. There were no significant differences in attrition between OBF and FQ at 180 days: adjusted hazard ratios were 1.17 (95% CI: 0.83, 1.65) among females and 1.23 (95% CI: 0.95, 1.58) among males. This study indicates that physically fit recruits who exceeded weight/body-fat standards were equally capable of serving at least 180 days compared to those who met standards.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.

OBJECTIVE: Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. METHODS: Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. RESULTS: A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1alpha- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean +/- SEM damage score 1.3 +/- 0.3, versus 2.2 +/- 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. CONCLUSION: The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.

Assessment of recruit motivation and strength study: preaccession physical fitness assessment predicts early attrition.

BACKGROUND: The Assessment of Recruit Motivation and Strength (ARMS) study was designed to pilot-test the use of a physical fitness screening tool for Army applicants before basic training. METHODS: The ARMS test consists of two components, namely, a 5-minute step test and push-ups. Attrition among 7,612 recruits who underwent preaccession ARMS testing and began service between May 2004 and December 2005 was studied. RESULTS: ARMS test performance was found to be significantly related to risk of attrition within 180 days; the hazard ratios for failing relative to passing the ARMS test were 2.27 (95% confidence interval, 1.70-3.04) among female subjects and 1.36 (95% confidence interval, 1.13-1.64) among male subjects. The attributable risk of attrition associated with failing the ARMS test was approximately 40% among female subjects and approximately 30% among male subjects. DISCUSSION: The ARMS study is the first prospective study conducted in the U.S. Army to assess physical fitness before accession. Physical fitness and motivation to serve were shown to correlate with attrition during initial entry training.

Retention of mild asthmatics in the navy (REMAIN): a low-risk approach to giving mild asthmatics an opportunity for military service.

OBJECTIVE: Rising U.S. asthma prevalence will be reflected in military applicants. We studied retaining mild asthmatics on active duty. METHODS: A cohort study at Great Lakes Naval Training Center from 2000 to 2002 compared recruits diagnosed during basic training with mild asthma to matched comparison recruits on outpatient visits, hospitalizations, and discharge through August 2003. RESULTS: A total of 136 asthmatic and 404 control subjects were enrolled. Overall attrition was greater among the asthma cohort (p < 0.01), largely during training. Asthmatics used more health care than controls during training (0.1 vs. 0.004 per person-month). No asthma-related hospitalizations or deaths occurred during the study. CONCLUSIONS: Although attrition during recruit training was higher in mild asthmatics, nearly 40% of recruits were retained on active duty without significant risk of hospitalization or excessive outpatient treatment after recruit training. These findings argue for consideration of a trial on active duty for recruits with mild asthma.

Attrition of U.S. military enlistees with waivers for hearing deficiency, 1995-2004.

BACKGROUND: Hearing deficiency is the condition for which accession medical waivers are most commonly granted. The retention of individuals entering service with a waiver for hearing deficiency has not been previously studied. METHODS: Military retention among new enlistees with a medical waiver for hearing deficiency was compared with that among a matched comparison group of fully qualified enlistees. Comparisons according to branch of service over the first 3 years of service were performed with the Kaplan-Meier product-limit method and proportional-hazards model. RESULTS: Army subjects had significantly lower retention rates than did their fully qualified counterparts. In the adjusted model, Army and Navy enlistees with a waiver for hearing deficiency had a significantly lower likelihood of retention than did their matched counterparts. DISCUSSION: The increased likelihood of medical attrition in enlistees with a waiver for hearing loss provides no evidence to make the hearing accession standard more lenient and validates a selective hearing loss waiver policy.

A review of initial entry training discharges at Fort Leonard Wood, MO, for accuracy of discharge classification type: fiscal year 2003.

OBJECTIVE: This study examines the extent to which discharges from Initial Entry Training can be adequately characterized by the current policy of a single descriptive category. METHODS: Service records of each trainee discharged from Fort Leonard Wood in 2003 were examined. Discharged trainee's counseling and outpatient clinic visit records were reviewed for evidence of multiple reasons for discharge. RESULTS: Evidence of medical involvement was found by record review in 13% of administrative discharges. Among discharges classified as being for medical or physical conditions that did not exist before service, 17% had clear evidence of preexisting chronic conditions. CONCLUSION: The policy of allowing only one categorization code to describe reasons for an Initial Entry Training discharge frequently resulted in incomplete characterization of factors leading to discharge. Pre-existing medical and mental health conditions were found in a much greater percentage of discharges than indicated by a simple review of discharge codes.

Attrition of military enlistees with a medical waiver for myopia, 1999-2001.

BACKGROUND: Military service requires physical fitness, including vision within set standards. Premature attrition inflicts a considerable manpower and fiscal burden upon the military. METHODS: We conducted a retrospective cohort survival analysis of newly enlisted military personnel who entered active duty with a medical waiver for myopia between January 1, 1999, and December 31, 2001. Premature attrition rates, both medical and overall, were compared with those for a matched, fully qualified, comparison group. RESULTS: New enlistees with a waiver for myopia had the same probability of remaining on active duty through the first 2 years of service as did fully qualified peers. Enlistees with a waiver for myopia also had a low probability of an early medical discharge for myopia. CONCLUSION: The results of this study tend to validate the current branch-specific myopia waiver processes. They also provide evidence that current myopia accession criteria may be too restrictive and in need of policy review.

Adjacent segment disc pressures following two-level cervical disc replacement versus simulated anterior cervical fusion.

Anterior cervical fusion (ACF) has been shown to alter the biomechanics of adjacent segments of the cervical spine. The goal of total disc replacement is to address pathology at a given disc with minimal disruption of the operated or adjacent segments. This study compares the pressure within discs adjacent to either a two-level simulated ACDF or a two-level total disc replacement with the ProDisc-C. A special automated motion testing apparatus was constructed. Four fresh cadaveric cervical spine specimens were affixed to the test stand and tested in flexion and extension under specific loads. Intradiscal, miniature strain-gauge-based transducers were placed in the discs above and below the "treated" levels. The specimens were then tested in flexion and extension. Pressure and overall angular displacement were measured. In the most extreme and highest quality specimen the difference at C3/C4 registered 800 kPa and the difference at C6/C7 registered 50 kPa. This same quality specimen treated with the ProDisc reached a flexion angle at much lower moments, 24.3 degrees at 5 N-m, when compared to the the SACF 12.2 degrees at 8.6 N-m. Therefore, the moment needed to achieve 15 degrees of flexion with the SACF treatment was 5.5 N-m and the ProDisc treatment was only 2.9 N-m. This initial data would indicate that adjacent level discs experience substantially lower pressure after two-level disc replacement when compared to two-level SACF. Additional testing to further support these observations is ongoing.

Accession standards for attention-deficit/hyperactivity disorder: a survival analysis of military recruits, 1995-2000.

A retrospective cohort study was conducted to evaluate the Department of Defense practice of allowing some individuals with a history of attention-deficit/hyperactivity disorder (ADHD) to enter military service (waiving for ADHD). Enlisted recruits who entered active duty with a waiver for academic problems related to ADHD were compared with control subjects who did not reveal health problems before entry, in terms of retention, promotion, and mental health-related outcomes. A total of 539 recruits with a history of ADHD were retained at the same rate as 1,617 control subjects, with no differences in promotion rates, comorbid diagnoses, or mental health-related discharges. On the basis of these findings, the Department of Defense medical accession standards have been changed to allow applicants who reveal a history of ADHD but did not require medication to finish high school or to hold a job for at least 1 year the opportunity to enter active duty without going through the current waiver process.

Attrition of military enlistees with a medical waiver for chronic headache, 1995-2000.

BACKGROUND: Recurrent headaches are disqualifying for military service if they are of sufficient severity or frequency to interfere with normal function in the past 3 years. The occupational impact of waiving this standard is evaluated. METHODS: A retrospective cohort study of enlistees from January 1, 1995, through December 31, 2000, was performed. Enlistees with a waiver for recurrent headaches were compared with fully qualified enlistees (matched 3:1) for retention in the military, headache-related discharges, and hospitalizations. RESULTS: The 174 individuals with waivers for a history of recurrent headaches were retained on active duty at the same rate as the 522 matched control subjects (log rank test, p = 0.91). Medical record review of waivers documented no debilitating headaches within 1 year before the medical examination. CONCLUSIONS: These results validate the current headache waiver criteria from the perspective of retention and suggest a more lenient medical accession standard. Future studies should evaluate the morbidity and occupational impact of headaches in the U.S. military.

Beryllium and lung cancer: a reanalysis of a NIOSH cohort mortality study.

This analysis is motivated by recent reviews on the carcinogenicity of beryllium by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the American Conference of Governmental Industrial Hygienists, and reconsideration by the National Toxicology Program on its classification of the carcinogenicity of beryllium. It reanalyzes data from a 1992 publication of a cohort mortality study conducted by the National Institute of Occupational Safety and Health (NIOSH) of workers employed in seven plants producing beryllium in the United States (Ward et al., 1992). That publication reported an increased risk of lung cancer in these workers and concluded that it is most likely due to occupational exposure to beryllium compounds. This present report uses: (1) an adjustment for smoking based on more germane estimates of the association between smoking and mortality from lung cancer; (2) computations of expected lung cancer rates based on alternative comparison populations; and (3) an overall combined estimate of the findings from the individual plants based on meta-analysis. Our findings indicate lower and generally not statistically significant standard mortality ratios that are not compatible with the interpretation of a likely causal association.

Hospitalization rates in female US Army recruits associated with a screening program for Chlamydia trachomatis.

BACKGROUND: A volunteer program to test non-healthcare-seeking women for genital Chlamydia trachomatis infection was instituted at the US Army's largest basic training center and evaluated for its effectiveness in reducing sequelae. GOAL: To compare hospitalization rates between women with positive test results for C trachomatis and those with negative results, and between women tested and those not tested for C trachomatis. STUDY DESIGN: For this study, 28,074 women who entered the Army in 1996 and 1997 were followed for hospitalizations through December 1998. Of these women, 7053 were tested for C trachomatis, and 21,021 were not screened. Hospital admissions were calculated per person-year, and adjusted relative risks were determined. RESULTS: The overall prevalence of C trachomatis in the screened group was 9.1%. The relative risk of hospitalization for pelvic inflammatory disease in the screened cohort was 0.94 (95% CI, 0.69-1.29), as compared with those not screened. The relative risk of hospitalization for any reason was 0.94 (95% CI, 0.90-0.99). Among women screened, no difference was found in pelvic inflammatory disease hospitalizations between women with positive test results who were being treated for C trachomatis and those with negative test results. CONCLUSIONS: The investigated C trachomatis intervention program for female Army recruits was associated with a lower overall hospitalization rate in screened volunteers, as compared with unscreened women. The pelvic inflammatory disease hospitalization rate in women with C trachomatis who were screened and treated was similar to that observed in uninfected women.

Solid-Phase Synthesis and Encoding Strategies for Olefin Polymerization Catalyst Libraries.

Active polymerization catalysts, novel resin-bound diimine complexes of nickel(II) and palladium(II) are obtained by combinatorial synthesis and combined in a catalyst library. By tagging with fluorescent markers, the catalysts can be coded. Therefore, after cleavage of the tag from the polymer-coated resin, HPLC can be used to determine the pathway along which the products were formed.