Analysis of the non-Markov parameter in continuous-time signal processing.

The use of statistical complexity metrics has yielded a number of successful methodologies to differentiate and identify signals from complex systems where the underlying dynamics cannot be calculated. The Mori-Zwanzig framework from statistical mechanics forms the basis for the generalized non-Markov parameter (NMP). The NMP has been used to successfully analyze signals in a diverse set of complex systems. In this paper we show that the Mori-Zwanzig framework masks an elegantly simple closed form of the first NMP, which, for C(1) smooth autocorrelation functions, is solely a function of the second moment (spread) and amplitude envelope of the measured power spectrum. We then show that the higher-order NMPs can be constructed in closed form in a modular fashion from the lower-order NMPs. These results provide an alternative, signal processing-based perspective to analyze the NMP, which does not require an understanding of the Mori-Zwanzig generating equations. We analyze the parametric sensitivity of the zero-frequency value of the first NMP, which has been used as a metric to discriminate between states in complex systems. Specifically, we develop closed-form expressions for three instructive systems: band-limited white noise, the output of white noise input to an idealized all-pole filter,f and a simple harmonic oscillator driven by white noise. Analysis of these systems shows a primary sensitivity to the decay rate of the tail of the power spectrum.

Theoretical & experimental analysis of the Non Markov Parameter to detect low frequency synchronisation in time series analysis.

A theoretical investigation into the behaviour of the Non-Markov Parameter is performed from a signal processing perspective in contrast to previous methodologies based on stochastic processes theory. The results indicate that the NMP can be regarded as an informational metric which is indicative of the degree of low frequency synchronisation in a complex system. These results have deep implications for physiological analysis of biological systems where the presence of sychronisation is often a marker of pathological functioning. The NMP measure is then applied to in vivo micro-electrode recordings from the subthalamic nucleus.

The role of protein C, protein S, and resistance to activated protein C in Legg-Perthes disease.

OBJECTIVES: It has been hypothesized that Legg-Perthes disease is caused by repeated vascular interruptions of the blood supply to the proximal femur, which are precipitated by coagulation system abnormalities. To test this theory, we conducted a case-control study among 57 patients with Legg-Perthes disease and an equal number of community controls. We measured protein C and protein S and resistance to activated protein C (APC-R) from plasma. STUDY DESIGN: Participants were placed into 1 of 3 mutually exclusive categories based on the control distribution: 1) normal, defined as either above or within 1 standard deviation below the expected mean; 2) low normal, defined as between 1 and 2 standard deviations below the expected mean; and 3) low, defined as >2 standard deviations below the expected mean. DNA was analyzed to determine the presence of a point mutation in the factor V gene that causes APC-R. RESULTS: We observed a statistically significant increased risk of Legg-Perthes disease with decreasing levels of protein C and a nearly significant increased risk with decreasing levels of protein S. The factor V gene defect was present in 5 (9%) of 55 cases and 3 (5%) of 56 controls (odds ratio 1.8, 95% confidence interval: 0.4-7.7), but the mean level on the APC-R plasma test was similar for cases and controls. Nine cases and 1 control had 2 low normal or low test results (odds ratio 13.0, 95% confidence interval: 2.2-75). CONCLUSIONS: Our results support the belief that abnormalities of the coagulation system leading to a thrombophilic state play a role in Legg-Perthes disease; however, larger studies are needed before definitive recommendations for coagulation testing can be made.

A stochastic differential equation model of diurnal cortisol patterns.

Circadian modulation of episodic bursts is recognized as the normal physiological pattern of diurnal variation in plasma cortisol levels. The primary physiological factors underlying these diurnal patterns are the ultradian timing of secretory events, circadian modulation of the amplitude of secretory events, infusion of the hormone from the adrenal gland into the plasma, and clearance of the hormone from the plasma by the liver. Each measured plasma cortisol level has an error arising from the cortisol immunoassay. We demonstrate that all of these three physiological principles can be succinctly summarized in a single stochastic differential equation plus measurement error model and show that physiologically consistent ranges of the model parameters can be determined from published reports. We summarize the model parameters in terms of the multivariate Gaussian probability density and establish the plausibility of the model with a series of simulation studies. Our framework makes possible a sensitivity analysis in which all model parameters are allowed to vary simultaneously. The model offers an approach for simultaneously representing cortisol's ultradian, circadian, and kinetic properties. Our modeling paradigm provides a framework for simulation studies and data analysis that should be readily adaptable to the analysis of other endocrine hormone systems.

Epidemiological features of and public health response to a St. Louis encephalitis epidemic in Florida, 1990-1.

A St. Louis encephalitis (SLE) epidemic in Florida during 25 weeks in 1990-1, resulted in 222 laboratory-diagnosed cases, an attack rate in the 28 affected counties of 2.25/100,000. Disease risk rose with advanced age, to 17.14/100,000 in persons over 80 years, and all 14 fatal cases were in persons over 55 years (median, 70 years). Community serosurveys in Indian River County, the epicenter of the outbreak (attack rate 21/100,000), showed acute asymptomatic infections in 3.6% of the persons surveyed, with higher rates in persons with outdoor occupational exposure (7.4%) and in clients of a shelter for the indigent (13.3%). A matched case-control study found that evening outdoor exposure for more than 2 h was associated with an increased risk for acquiring illness (odds ratio [OR] 4.33, 95% CI 1.23-15.21) while a number of recommended personal protective measures were protective. Four SLE patients were dually infected with Highlands J virus, the first reported cases of acute infection with this alphavirus. The case-control study provided the first evidence that a public education campaign to reduce exposure had a protective effect against acquiring the disease.

Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260).

The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team.

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.

Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258.

BACKGROUND: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. OBJECTIVE: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. DESIGN: Phase I study. SETTING: Four clinical research units. PATIENTS: 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. INTERVENTION: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. MEASUREMENTS: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. RESULTS: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. CONCLUSIONS: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied.

Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients.

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.

Public health response for the 1996 Olympic Games.

Extensive planning and preparation by public health agencies were required for the provision of public health services during the 1996 Centennial Olympic Games, which brought together more than 10000 athletes from 197 countries and more than 2 million visitors. Public health activities included the development and use of an augmented surveillance system to monitor health conditions and detect disease outbreaks; creation and implementation of 6 environmental health regulations; establishment of a central Public Health Command Center and response teams to coordinate response to public health emergencies; planning for potential mass casualties and the provision of emergency medical services; implementation of strategies for the prevention of heat-related illness; and distribution of health promotion and disease prevention information. Public health agencies should take the lead in organizing and implementing a system for preventing and managing public health issues at future large-scale public events such as the Olympics.

Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. AIDS Clinical Trials Group Study 197.

We conducted a three-arm, randomized, phase II study to evaluate the combination of zidovudine (600 mg/day) and zalcitabine (2.25 mg/day) alone or with one of two interferon-alpha2a doses (1 mIU or 6 mIU daily). Primary study endpoints included toxicity and changes from baseline for plasma HIV-1 RNA, CD4 cells, and quantitative microculture at weeks 8 and 24. Sixty-three patients with HIV infection and <400 CD4 cells/mm3 were enrolled; four patients discontinued therapy within 2 weeks. Adverse event rates were 37%, 32%, and 60%, respectively, for the nucleoside, 1-mIU interferon, and 6-mIU interferon combination groups. Increasing doses of interferon resulted in significantly greater hematologic toxicity (p = 0.03) and peripheral neuropathy (p = 0.02). Plasma HIV-1 RNA reductions were noted across all treatment groups at week 8 (p < 0.001) but only for the nucleoside and 1-mIU interferon combination groups at week 24 (p < 0.001). Mean reductions in HIV-1 RNA at week 8 were 0.94, 1.29, and 1.40 log10, respectively, for the nucleoside, 1-mIU interferon, and 6-mIU interferon combination groups (p = 0.05); no differences were noted at week 24. No differences in CD4 cell counts were seen. The addition of interferon-alpha2a to zidovudine and zalcitabine resulted in transient enhanced decreases in viral load and increased toxicity.

Phase I/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151.

SC-52151, an HIV-1 protease inhibitor, was developed as an ethanol-based elixir and subsequently as a self-emulsifying drug delivery system (SEDDS) to improve bioavailability. To evaluate formulation and treatment regimen effects, we conducted a four-arm, phase I/II study using the highest previously tested daily dose, 2250 mg. Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily or 1125 mg twice daily for 14 days. One patient developed hypertriglyceridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-time curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HIV. A mean decline of 0.03 log10 RNA copies (SEDDS) and an increase of 0.15 log10 (elixir) were observed. Although SC-52151 was well tolerated and the SEDDS formulation resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced.

HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine.

Previous studies have shown that the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase mutation Y181C, which confers high-level resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), develops rarely during therapy with NNRTIs plus zidovudine. To determine whether didanosine (ddI) is also effective in preventing the emergence of Y181C, we analyzed delavirdine (DLV) susceptibilties and reverse transcriptase sequences of isolates obtained from patients enrolled in a pharmacokinetic study of DLV and ddI. Nine NNRTI-naive patients were evaluated. Seven received DLV/ddI and two received DLV/ddI/zidovudine. Median durations of prior zidovudine and ddI were 26 and 15 months, respectively. Isolates from eight of nine patients had a mutation(s) associated with nucleoside resistance at entry. After treatment with DLV and ddI alone, isolates from five of seven patients developed Y181C, four in combination with K103N. Thus, in this group of nucleoside-experienced patients, combination therapy with DLV/ddI did not prevent the emergence of Y181C.

A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team.

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.

Vertebral collapse in childhood leukemia.

Leukemia is the most common form of cancer in children. At the time of initial presentation, 10% of children have normal peripheral blood counts. Appendicular skeletal involvement occurs in approximately 50% of cases. The literature does not clearly define the incidence of spinal involvement, with only a total of 31 cases located in a review of the literature. If case reports are excluded and series that reported the frequency of spinal involvement are summarized, only 16 of 615 cases had spinal involvement. In only one of 31 was it clear that the patient had a normal peripheral blood count at the time of diagnosis. This article adds to the literature two patients who had normal peripheral blood counts and spinal involvement with acute lymphocytic leukemia. Patients with leukemia may have significant symptoms and radiographic signs with normal peripheral cell blood counts at the time of initial presentation.

The emergency department in surveillance of attempted suicide: findings and methodologic considerations.

The authors conducted one of the first active, population-based public health surveillance systems for detecting suicide attempts in the United States. Surveillance was conducted in all four hospital emergency departments serving a county suburban to Atlanta, GA, with a population of 426,000. Emergency department staff gathered information from all patients who presented with an intentionally self-inflicted injury (suicide attempt) or with thoughts about self-injury (suicidal ideation). During an 18-month period in 1988 and 1989, 798 suicide attempt-related patients were reported, for a rate of 124.7 per 100,000 county residents per year. Females had a higher attempted suicide rate than males, but males had a higher completed suicide rate. Ingestion of drugs or poison was the most common method of attempted suicide (71.1 percent), and use of firearms was the most common method of completed suicide (69.8 percent). In comparing reported cases with those found by reviewing emergency department log books, the authors found that the case reports were 58 percent complete and that surveillance reporting was highly representative of all cases requiring emergency transport. The authors conclude that emergency department-based surveillance for attempted suicide is feasible. It can provide representative data that may be used to monitor trends in attempted suicide and to define high-risk groups. Such surveillance may also allow timely detection of suicide attempt clusters, facilitating prompt intervention.

A foodborne outbreak of gastroenteritis involving two different pathogens.

On the evening of October 10, 1990, many of the 474 inmates of a state prison in Florida began to experience symptoms of gastroenteritis. An investigation included interviews with inmates, evaluation of the kitchen and food-handling practices, cultures of leftover food, stool cultures, and cultures from the nares and skin lesions of food handlers. Of the 331 inmates interviewed, 215 (65%) had diarrhea, vomiting, or both. The median incubation period was 5 hours (range, 1-41 hours). Cases with onset of illness 8 or more hours after the evening meal were more likely than those with earlier onset to have had only diarrhea without vomiting (p < 0.001). Eating turkey at the evening meal on October 10 was associated with risk of illness (relative risk = 4.8, 95% confidence interval 1.7-13.7). Cases who became ill within 8 hours of the evening meal and those who became ill later were both more likely to have eaten turkey than those who did not become ill (p < 0.001 and p < 0.007, respectively). Salmonella infantis and enterotoxin-producing Staphylococcus aureus were both isolated from samples of leftover turkey, and S. infantis was isolated from 18 of 20 stool specimens. Cultures of the anterior nares and skin lesions of food handlers grew S. aureus, but phage typing failed to link these strains to the outbreak. Improper food-handling practices contributed to the development of this outbreak. This report highlights the importance of recognizing multiple-organism outbreaks, since the authors' recommendations for prevention of more cases depended upon knowing the risks associated with the distinct organisms and the possible sources of contamination.