Escalating costs of self-injury mortality in the 21st century United States: an interstate observational study.

BACKGROUND: Estimating the economic costs of self-injury mortality (SIM) can inform health planning and clinical and public health interventions, serve as a basis for their evaluation, and provide the foundation for broadly disseminating evidence-based policies and practices. SIM is operationalized as a composite of all registered suicides at any age, and 80% of drug overdose (intoxication) deaths medicolegally classified as 'accidents,' and 90% of corresponding undetermined (intent) deaths in the age group 15 years and older. It is the long-term practice of the United States (US) Centers for Disease Control and Prevention (CDC) to subsume poisoning (drug and nondrug) deaths under the injury rubric. This study aimed to estimate magnitude and change in SIM and suicide costs in 2019 dollars for the United States (US), including the 50 states and the District of Columbia. METHODS: Cost estimates were generated from underlying cause-of-death data for 1999/2000 and 2018/2019 from the US Centers for Disease Control and Prevention's (CDC's) Wide-ranging ONline Data for Epidemiologic Research (WONDER). Estimation utilized the updated version of Medical and Work Loss Cost Estimation Methods for CDC's Web-based Injury Statistics Query and Reporting System (WISQARS). Exposures were medical expenditures, lost work productivity, and future quality of life loss. Main outcome measures were disaggregated, annual-averaged total and per capita costs of SIM and suicide for the nation and states in 1999/2000 and 2018/2019. RESULTS: 40,834 annual-averaged self-injury deaths in 1999/2000 and 101,325 in 2018/2019 were identified. Estimated national costs of SIM rose by 143% from $0.46 trillion to $1.12 trillion. Ratios of quality of life and work losses to medical spending in 2019 US dollars in 2018/2019 were 1,476 and 526, respectively, versus 1,419 and 526 in 1999/2000. Total national suicide costs increased 58%-from $318.6 billion to $502.7 billion. National per capita costs of SIM doubled from $1,638 to $3,413 over the observation period; costs of the suicide component rose from $1,137 to $1,534. States in the top quintile for per capita SIM, those whose cost increases exceeded 152%, concentrated in the Great Lakes, Southeast, Mideast and New England. States in the bottom quintile, those with per capita cost increases below 70%, were located in the Far West, Southwest, Plains, and Rocky Mountain regions. West Virginia exhibited the largest increase at 263% and Nevada the smallest at 22%. Percentage per capita cost increases for suicide were smaller than for SIM. Only the Far West, Southwest and Mideast were not represented in the top quintile, which comprised states with increases of 50% or greater. The bottom quintile comprised states with per capita suicide cost increases below 24%. Regions represented were the Far West, Southeast, Mideast and New England. North Dakota and Nevada occupied the extremes on the cost change continuum at 75% and - 1%, respectively. CONCLUSION: The scale and surge in the economic costs of SIM to society are large. Federal and state prevention and intervention programs should be financed with a clear understanding of the total costs-fiscal, social, and personal-incurred by deaths due to self-injurious behaviors.

Clinical phenotypes and therapeutic responses in cutaneous-predominant sarcoidosis: 6-year experience in a tertiary referral service.

BACKGROUND: There is a limited evidence base for the treatment of cutaneous sarcoidosis. OBJECTIVE: To describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease. METHODS: Data were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness. RESULTS: In total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission. CONCLUSION: HCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.

ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway.

BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

A randomized trial on subject tolerance and the adverse effects associated with higher- versus lower-flow oxygen through a standard nasal cannula.

STUDY OBJECTIVE: Experts advocate the use of a standard nasal cannula to provide oxygen at flow rates of up to 15 L/minute during emergency intubation. However, because of concerns about potential patient discomfort, some providers avoid providing nasal cannula oxygen at flow rates greater than 6 L/minute. This trial is designed to determine the participants' ability to tolerate 10 minutes of nasal cannula oxygen at higher flow rates. METHODS: This was a prospective, randomized, crossover trial of healthy volunteers at an emergency department in New Zealand. Participants were randomized to first receive either higher-flow (15 L/minute) or lower-flow (6 L/minute) nasal cannula oxygen for 10 minutes. After a 1-hour washout period, they received the alternate flow rate for 10 minutes. The primary outcome was the ability to tolerate 10 minutes of the nasal cannula oxygen at each flow rate. The secondary outcome was the difference in discomfort between the flow rates as measured on a 100-mm visual analog scale. RESULTS: All 77 of the participants (100%) were able to tolerate 10 minutes at both flow rates. Participants rated the higher-flow nasal cannula oxygen as a mean of 25 mm (SD 20 mm) more uncomfortable than the lower-flow nasal cannula oxygen. One minute after the oxygen was discontinued, the mean difference in discomfort between the flow rates was a clinically insignificant 9.8 mm (SD 17 mm) more uncomfortable. There were no adverse events. CONCLUSION: Participants were able to tolerate higher-flow nasal cannula oxygen for 10 minutes without difficulty. Higher-flow nasal cannula oxygen at 15 L/minute was associated with some discomfort, but the discomfort quickly dissipated and caused no adverse events.

Confronting death from drug self-intoxication (DDSI): prevention through a better definition.

Suicide and other self-directed violence deaths are likely grossly underestimated, reflecting inappropriate classification of many drug intoxication deaths as accidents or unintentional and heterogeneous ascertainment and coding practices across states. As the tide of prescription and illicit drug-poisoning deaths is rising, public health and research needs would be better satisfied by considering most of these deaths a result of self-intoxication. Epidemiologists and prevention scientists could design better intervention strategies by focusing on premorbid behavior. We propose incorporating deaths from drug self-intoxication and investigations of all poisoning deaths into the National Violent Death Reporting System, which contains misclassified homicides and undetermined intent deaths, to facilitate efforts to comprehend and reverse the surging rate of drug intoxication fatalities.

Association of State Social and Environmental Factors With Rates of Self-injury Mortality and Suicide in the United States.

Importance: Self-injury mortality (SIM) combines suicides and the preponderance of drug misuse-related overdose fatalities. Identifying social and environmental factors associated with SIM and suicide may inform etiologic understanding and intervention design. Objective: To identify factors associated with interstate SIM and suicide rate variation and to assess potential for differential suicide misclassification. Design, Setting, and Participants: This cross-sectional study used a partial panel time series with underlying cause-of-death data from 50 US states and the District of Columbia for 1999-2000, 2007-2008, 2013-2014 and 2018-2019. Applying data from the Centers for Disease Control and Prevention, SIM includes all suicides and the preponderance of unintentional and undetermined drug intoxication deaths, reflecting self-harm behaviors. Data were analyzed from February to June 2021. Exposures: Exposures included inequity, isolation, demographic characteristics, injury mechanism, health care access, and medicolegal death investigation system type. Main Outcomes and Measures: The main outcome, SIM, was assessed using unstandardized regression coefficients of interstate variation associations, identified by the least absolute shrinkage and selection operator; ratios of crude SIM to suicide rates per 100 000 population were assessed for potential differential suicide misclassification. Results: A total of 101 325 SIMs were identified, including 74 506 (73.5%) among males and 26 819 (26.5%) among females. SIM to suicide rate ratios trended upwards, with an accelerating increase in overdose fatalities classified as unintentional or undetermined (SIM to suicide rate ratio, 1999-2000: 1.39; 95% CI, 1.38-1.41; 2018-2019: 2.12; 95% CI, 2.11-2.14). Eight states recorded a SIM to suicide rate ratio less than 1.50 in 2018-2019 vs 39 states in 1999-2000. Northeastern states concentrated in the highest category (range, 2.10-6.00); only the West remained unrepresented. Least absolute shrinkage and selection operator identified 8 factors associated with the SIM rate in 2018-2019: centralized medical examiner system (ß = 4.362), labor underutilization rate (ß = 0.728), manufacturing employment (ß = -0.056), homelessness rate (ß = -0.125), percentage nonreligious (ß = 0.041), non-Hispanic White race and ethnicity (ß = 0.087), prescribed opioids for 30 days or more (ß = 0.117), and percentage without health insurance (ß = -0.013) and 5 factors associated with the suicide rate: percentage male (ß = 1.046), military veteran (ß = 0.747), rural (ß = 0.031), firearm ownership (ß = 0.030), and pain reliever misuse (ß = 1.131). Conclusions and Relevance: These findings suggest that SIM rates were associated with modifiable, upstream factors. Although embedded in SIM, suicide unexpectedly deviated in proposed social and environmental determinants. Heterogeneity in medicolegal death investigation processes and data assurance needs further characterization, with the goal of providing the highest-quality reports for developing and tracking public health policies and practices.

Fatal self-injury in the United States, 1999-2018: Unmasking a national mental health crisis.

BACKGROUND: Suicides by any method, plus 'nonsuicide' fatalities from drug self-intoxication (estimated from selected forensically undetermined and 'accidental' deaths), together represent self-injury mortality (SIM)-fatalities due to mental disorders or distress. SIM is especially important to examine given frequent undercounting of suicides amongst drug overdose deaths. We report suicide and SIM trends in the United States of America (US) during 1999-2018, portray interstate rate trends, and examine spatiotemporal (spacetime) diffusion or spread of the drug self-intoxication component of SIM, with attention to potential for differential suicide misclassification. METHODS: For this state-based, cross-sectional, panel time series, we used de-identified manner and underlying cause-of-death data for the 50 states and District of Columbia (DC) from CDC's Wide-ranging Online Data for Epidemiologic Research. Procedures comprised joinpoint regression to describe national trends; Spearman's rank-order correlation coefficient to assess interstate SIM and suicide rate congruence; and spacetime hierarchical modelling of the 'nonsuicide' SIM component. FINDINGS: The national annual average percentage change over the observation period in the SIM rate was 4.3% (95% CI: 3.3%, 5.4%; p<0.001) versus 1.8% (95% CI: 1.6%, 2.0%; p<0.001) for the suicide rate. By 2017/2018, all states except Nebraska (19.9) posted a SIM rate of at least 21.0 deaths per 100,000 population-the floor of the rate range for the top 5 ranking states in 1999/2000. The rank-order correlation coefficient for SIM and suicide rates was 0.82 (p<0.001) in 1999/2000 versus 0.34 (p = 0.02) by 2017/2018. Seven states in the West posted a ≥ 5.0% reduction in their standardised mortality ratios of 'nonsuicide' drug fatalities, relative to the national ratio, and 6 states from the other 3 major regions a >6.0% increase (p<0.05). INTERPRETATION: Depiction of rising SIM trends across states and major regions unmasks a burgeoning national mental health crisis. Geographic variation is plausibly a partial product of local heterogeneity in toxic drug availability and the quality of medicolegal death investigations. Like COVID-19, the nation will only be able to prevent SIM by responding with collective, comprehensive, systemic approaches. Injury surveillance and prevention, mental health, and societal well-being are poorly served by the continuing segregation of substance use disorders from other mental disorders in clinical medicine and public health practice. FUNDING: This study was partially funded by the National Centre for Injury Prevention and Control, US Centers for Disease Control and Prevention (R49CE002093) and the US National Institute on Drug Abuse (1UM1DA049412-01; 1R21DA046521-01A1).

Women of child-bearing age have better inhospital cardiac arrest survival outcomes than do equal-aged men.

OBJECTIVES: Estrogen and progesterone improve neurologic outcomes in experimental models of cardiac arrest and stroke. Our objective was to determine whether women of child-bearing age are more likely than men to survive to hospital discharge after in-hospital cardiac arrest. DESIGN: Prospective, observational study. SETTING: Five hundred nineteen hospitals in the National Registry of Cardiopulmonary Resuscitation database. PATIENTS: Patients included 95,852 men and women 15-44 yrs and 56 yrs or older with pulseless cardiac arrests from January 1, 2000 through July 31, 2008. MEASUREMENTS AND MAIN RESULTS: Patients were stratified a priori by gender and age groups (15-44 yrs and > or =56 yrs). Fixed-effects regression conditioning on hospital was used to examine the relationship between age, gender, and survival outcomes. The unadjusted survival to discharge rate for younger women of child-bearing age (15-44 yrs) was 19% (940/4887) vs. 17% (1203/7025) for younger men (p = .013). The adjusted hospital discharge difference between these younger women and men was 2.8% (95% confidence interval, 1.0% to 4.6%; p = .002), and these younger women also had a 2.6% (95% confidence interval, 0.9% to 4.3%; p = .002) absolute increase in favorable neurologic outcome. For older women compared with men (> or =56 yrs), there were no demonstrable differences in discharge rates (18% vs. 18%; adjusted difference, -0.1%; 95% confidence interval, -0.9% to 0.6%; p = .68) or favorable neurologic outcome (14% vs. 14%; adjusted difference, -0.1%; 95% confidence interval, -0.7% to 0.5%; p = .74). CONCLUSIONS: Women of child-bearing age were more likely than comparably aged men to survive to hospital discharge after in-hospital cardiac arrest, even after controlling for etiology of arrest and other important variables.

Atropine 0.01% Eye Drops for Myopia Control in American Children: A Multiethnic Sample Across Three US Sites.

INTRODUCTION: Topical atropine eye drops at low concentrations have been shown to slow myopia progression in East Asian studies. This study explored the effect of atropine 0.01% eye drops on controlling myopia progression in a multiethnic cohort of children in the USA. METHODS: A multicenter retrospective case-control study (n = 198) quantified the effect of adding nightly atropine 0.01% eye drops to treatment as usual on the progression of childhood (ages 6-15 years) myopia. Cases included all children treated with atropine for at least 1 year. Controls were matched to cases on both age (± 6 months) and baseline spherical equivalent refraction (SER) (± 0.50 diopters, D) at treatment initiation. The primary endpoint was the average SER myopia progression after 1, 1.5, and 2 years of therapy. A secondary outcome was the percentage of subjects with a clinically significant worsening of myopia, defined as a greater than - 0.75 D SER increase in myopia. RESULTS: The average baseline SERs for the atropine (n = 100) and control (n = 98) groups were similar (- 3.1 ± 1.9 D and - 2.8 ± 1.6 D, respectively) (p = 0.23). The average SER increase from baseline was significantly less for the atropine group than the control group at year 1 (- 0.2 ± 0.8 D compared with - 0.6 ± 0.4 D, p < 0.001) and at year 2 (- 0.3 ± 1.1 D compared with - 1.2 ± 0.7 D, p < 0.001). Secondary analysis at year 2 revealed that 80% of the control group vs. 37% of the atropine group experienced clinically significant worsening myopia of at least - 0.75 D (p < 0.001). There were no major safety issues reported in either group. CONCLUSION: Similar to results reported in Asia, atropine 0.01% eye drops significantly reduced myopia progression in a cohort of US children over 2 years of treatment. FUNDING: Nevakar, Inc. Plain language summary available for this article.

Survival from in-hospital cardiac arrest during nights and weekends.

CONTEXT: Occurrence of in-hospital cardiac arrest and survival patterns have not been characterized by time of day or day of week. Patient physiology and process of care for in-hospital cardiac arrest may be different at night and on weekends because of hospital factors unrelated to patient, event, or location variables. OBJECTIVE: To determine whether outcomes after in-hospital cardiac arrest differ during nights and weekends compared with days/evenings and weekdays. DESIGN AND SETTING: We examined survival from cardiac arrest in hourly time segments, defining day/evening as 7:00 am to 10:59 pm, night as 11:00 pm to 6:59 am, and weekend as 11:00 pm on Friday to 6:59 am on Monday, in 86,748 adult, consecutive in-hospital cardiac arrest events in the National Registry of Cardiopulmonary Resuscitation obtained from 507 medical/surgical participating hospitals from January 1, 2000, through February 1, 2007. MAIN OUTCOME MEASURES: The primary outcome of survival to discharge and secondary outcomes of survival of the event, 24-hour survival, and favorable neurological outcome were compared using odds ratios and multivariable logistic regression analysis. Point estimates of survival outcomes are reported as percentages with 95% confidence intervals (95% CIs). RESULTS: A total of 58,593 cases of in-hospital cardiac arrest occurred during day/evening hours (including 43,483 on weekdays and 15,110 on weekends), and 28,155 cases occurred during night hours (including 20,365 on weekdays and 7790 on weekends). Rates of survival to discharge (14.7% [95% CI, 14.3%-15.1%] vs 19.8% [95% CI, 19.5%-20.1%], return of spontaneous circulation for longer than 20 minutes (44.7% [95% CI, 44.1%-45.3%] vs 51.1% [95% CI, 50.7%-51.5%]), survival at 24 hours (28.9% [95% CI, 28.4%-29.4%] vs 35.4% [95% CI, 35.0%-35.8%]), and favorable neurological outcomes (11.0% [95% CI, 10.6%-11.4%] vs 15.2% [95% CI, 14.9%-15.5%]) were substantially lower during the night compared with day/evening (all P values < .001). The first documented rhythm at night was more frequently asystole (39.6% [95% CI, 39.0%-40.2%] vs 33.5% [95% CI, 33.2%-33.9%], P < .001) and less frequently ventricular fibrillation (19.8% [95% CI, 19.3%-20.2%] vs 22.9% [95% CI, 22.6%-23.2%], P < .001). Among in-hospital cardiac arrests occurring during day/evening hours, survival was higher on weekdays (20.6% [95% CI, 20.3%-21%]) than on weekends (17.4% [95% CI, 16.8%-18%]; odds ratio, 1.15 [95% CI, 1.09-1.22]), whereas among in-hospital cardiac arrests occurring during night hours, survival to discharge was similar on weekdays (14.6% [95% CI, 14.1%-15.2%]) and on weekends (14.8% [95% CI, 14.1%-15.2%]; odds ratio, 1.02 [95% CI, 0.94-1.11]). CONCLUSION: Survival rates from in-hospital cardiac arrest are lower during nights and weekends, even when adjusted for potentially confounding patient, event, and hospital characteristics.

Validation of a brief observation period for patients with cocaine-associated chest pain.

BACKGROUND: Retrospective studies of patients with cocaine-associated chest pain suggest that a strategy of discharging patients from the emergency department after a 12-hour observation period if they do not have evidence of ischemia should be associated with a very low rate of complications. METHODS: We prospectively evaluated the safety of a 9-to-12-hour observation period in patients with cocaine-associated chest pain who were at low-to-intermediate risk of cardiovascular events. Consecutive patients who reported or tested positive for cocaine use and who received protocol-driven care in a chest-pain observation unit were included. Patients who had normal levels of troponin I, without new ischemic changes on electrocardiography, and who had no cardiovascular complications (dysrhythmias, acute myocardial infarction, or recurrent symptoms) during the 9-to-12-hour observation period were discharged from the unit. The main outcome was death from cardiovascular causes at 30 days. RESULTS: Three hundred forty-four patients with cocaine-associated chest pain were evaluated. Forty-two of these patients (12 percent) were directly admitted to the hospital. The study cohort comprised the remaining 302 patients. During the 30-day follow-up period, none of the patients died of a cardiovascular event (0 percent; 95 percent confidence interval, 0 to 0.99), and only 4 of the 256 patients for whom detailed follow-up data were available had a nonfatal myocardial infarction (1.6 percent; 95 percent confidence interval, 0.1 to 3.1). All four nonfatal myocardial infarctions occurred in patients who continued to use cocaine. CONCLUSIONS: Patients with cocaine-associated chest pain who do not have evidence of ischemia or cardiovascular complications over a 9-to-12-hour period in a chest-pain observation unit have a very low risk of death or myocardial infarction during the 30 days after discharge.

Increased cortisol in women with intimate partner violence-related posttraumatic stress disorder.

BACKGROUND: Alterations of hypothalamic-pituitary-adrenal (HPA) axis function and sympathetic-adrenal activity have been proposed as key factors in biological models of posttraumatic stress disorder (PTSD). METHODS: We examined neuroendocrine function in female survivors of intimate partner violence (IPV) with lifetime (current or remitted) PTSD (n=29) and in women who were exposed to IPV but never developed PTSD (n=20). Salivary cortisol was collected as a marker of HPA axis function at 1, 4, 9, and 11 h after awakening. Platelet epinephrine and norepinephrine were assayed as markers of sympathetic-adrenal activation. RESULTS: Women with lifetime PTSD had significantly higher cortisol levels across the day compared to abuse-exposed participants without PTSD, after controlling for age, depression, severity, and latency of abuse. There were no significant group differences in levels of platelet catecholamines. CONCLUSIONS: Elevated cortisol levels may be a biomarker of IPV-related lifetime PTSD, reflecting long-lasting changes associated with trauma-exposure or possibly a reflection of risk for PTSD in women.

Evaluation of a minor eye conditions scheme delivered by community optometrists.

BACKGROUND: The establishment of minor eye conditions schemes (MECS) within community optometric practices provides a mechanism for the timely assessment of patients presenting with a range of acute eye conditions. This has the potential to reduce waiting times and avoid unnecessary referrals to hospital eye services (HES). OBJECTIVE: To evaluate the clinical effectiveness, impact on hospital attendances and patient satisfaction with a minor eye service provided by community optometrists. METHODS: Activity and outcome data were collected for 12 months in the Lambeth and Lewisham MECS. A patient satisfaction questionnaire was given to patients at the end of their MECS appointment. A retrospective difference-in-differences analysis of hospital activity compared changes in the volume of referrals by general practitioners (GPs) from a period before (April 2011-March 2013) to after (April 2013-March 2015) the introduction of the scheme in Lambeth and Lewisham relative to a neighbouring area (Southwark) where the scheme had not been commissioned. Appropriateness of case management was assessed by consensus using clinical members of the research team. RESULTS: A total of 2123 patients accessed the scheme. Approximately two-thirds of patients (67.5%) were referred by their GP. The commonest reasons for patients attending for a MECS assessment were 'red eye' (36.7% of patients), 'painful white eye' (11.1%) and 'flashes and floaters' (10.2%). A total of 64.1% of patients were managed in optometric practice and 18.9% were referred to the HES; of these, 89.2% had been appropriately referred. First attendances to HES referred by GPs reduced by 26.8% (95% CI -40.5% to -13.1%) in Lambeth and Lewisham compared to Southwark. CONCLUSIONS: The Lambeth and Lewisham MECS demonstrates clinical effectiveness, reduction in hospital attendances and high patient satisfaction and represents a successful collaboration between commissioners, local HES units and primary healthcare providers.

Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Effects of single exposures to antiproliferative agents on ocular fibroblast-mediated collagen contraction.

PURPOSE: To determine the effects of short-duration treatments with 5-fluorouracil (5FU) and mitomycin-c (MMC) on "activated" and "nonactivated" ocular fibroblasts in collagen lattices. METHODS: Activated and nonactivated ocular fibroblasts seeded in collagen lattices were exposed to single 5-minute treatments with 5FU (0.01 to 25 mg/ml) and MMC (0.01 to 1 mg/ml). The effects of these treatments on lattice contraction, cellularity, cellular viability, cellular structure, and actin distribution were investigated. RESULTS: Treatment with 5FU (0.01 to 25 mg/ml) or MMC (0.1 to 1 mg/ml) significantly inhibited (P < 0.001 and P < 0.0001, respectively) lattice contraction compared to water controls. The degree of inhibition was greater in lattices containing nonactivated cells than in those containing activated cells. Activated cell viability and cellularity, unlike their nonactivated counterparts, were not significantly affected (P > 0.0083) by treatment with 5FU at high concentrations (25 mg/ml). MMC treatment had significant effects on cell viability and cellularity (P < 0.0001). Treatment with 5FU and MMC also affected cellular structure and actin distribution compared to water controls. CONCLUSIONS: Single, short exposures to 5FU or MMC inhibit ocular fibroblast-mediated collagen contraction. MMC causes cell death and a decrease in cellularity at high concentrations. The results also indicate that collagen lattices seeded with activated and nonactivated fibroblasts are differentially affected by short-term exposures to 5FU or MMC. These findings may have important clinical implications regarding the concentrations of these agents used in the treatment of different patient groups.

Congenital malaria in a hyperendemic area.

The prevalence of Plasmodium falciparum malaria was evaluated in all near-term pregnant women and their newborns at the Macha Hospital in the Southern Province of Zambia during part of the rainy season, when malaria prevalence is at its peak. Peripheral parasitemia was noted in 19 (29%) of 65 newborns and in 40 (63%) of 63 mothers. All but one of the infected neonates had an infected mother, and 17 of 40 infected mothers gave birth to infected newborns. The parasite densities measured were uniformly low (less than 25,000/cc), and only seven of 19 infected neonates had fever within 48 hours of delivery suggestive of malaria infection. Parasitized newborns had a 469-gm lower average birthweight, but they did not have a higher incidence of prematurity or preterm delivery compared with uninfected newborns. In addition, the Apgar scores of infected and uninfected newborns were not significantly different. There was no correlation between neonatal parasitemia and either the sex of the child or the parity of the mother. Maternal chloroquine prophylaxis did not appear to be effective in preventing infection in the fetus or the gravida, and the emergence of chloroquine resistance may explain, in part, the greater prevalence of congenital malaria in endemic areas in recent years.

Depletion of O6-alkylguanine-DNA alkyltransferase activity in mammalian tissues and human tumor xenografts in nude mice by treatment with O6-methylguanine.

We have previously shown that exposure of cells in culture to O6-methylguanine significantly reduces their level of the repair protein, O6-alkylguanine-DNA-alkyltransferase (AGT), thus rendering cells more sensitive to the cytotoxic effects of chemotherapeutic chloroethylating agents. Experiments were carried out in mice to determine whether the AGT content of tissues and tumors could be reduced by in vivo treatment with O6-methylguanine. There was a dose-dependent decrease in AGT activity in liver tissues of CD-1 mice to 24% of basal levels after four hourly intraperitoneal injections of O6-methylguanine (110 mg/kg). Although the decline in AGT activity in the liver was reversible, the activity remained at 75% of basal levels for up to 25 h after the final injection. The effect of O6-methylguanine treatment on AGT activity was measured in mouse tissues as well as human colonic carcinoma tumors (HT29 and BE) grown in Swiss athymic nude mice. The activity in the liver, kidney, and spleen of these mice decreased to 33%-35% of control levels, whereas the activity in HT29 tumors was likewise diminished to 25% of control levels after four hourly injections of O6-methylguanine (100 mg/kg). There was no enhancement of the tumoricidal effectiveness of chloroethylating agents on the HT29 tumor after O6-methylguanine treatment, probably due to a disproportionately higher level of AGT in human tissue than in murine tissue. However, these studies suggest that O6-methylguanine can be given in vivo to examine the role of the AGT protein in protecting against the toxic and carcinogenic effects of alkylating agents.

Effectiveness of ignition interlock devices in reducing drunk driving recidivism.

OBJECTIVE: To determine if ignition interlock devices reduce driving while intoxicated (DWI) recidivism. SEARCH STRATEGIES: Cochrane Collaboration search strategies were used. SELECTION CRITERIA: Studies for selection examined the effectiveness of interlock programs in a defined population. Studies were required to have a clear description of the program and outcomes evaluated, to have a comparison group and to provide interpretable data. DATA COLLECTION AND ANALYSIS: A total of 31 studies were found. Ten studies met the selection criteria. Three of these studies were eliminated from further analysis because they did not contain original data. A fourth study was eliminated due to methodologic weaknesses, leaving six studies for final review and analysis. Pooled analyses were not done because studies did not follow similar methods over comparable time periods. MAIN RESULTS: Five of the six studies found interlocks were effective in reducing DWI recidivism while the interlock was installed in the car. In the five studies demonstrating a significant effect, participants in the interlock programs were 15%-69% less likely than controls to be re-arrested for DWI. The only reported randomized, controlled trial demonstrated a 65% reduction in re-arrests for DWI in the interlock group, compared with the control group. CONCLUSIONS: Alcohol ignition interlock programs appear to be effective in reducing DWI recidivism during the time period when the interlock is installed in the car. Future studies should attempt to control for exposure (i.e., number of miles driven) and determine if certain sub-groups are most benefited by interlock programs.

Persistent superior oblique paresis as a manifestation of familial periodic cerebellar ataxia.

A brother and sister complained of persistent diplopia due to superior oblique palsies. The cause of their symptoms became apparent when they were diagnosed as having familial periodic cerebellar ataxia (FPCA), a rare autosomal dominant condition. Oral acetazolamide (250 mg twice daily) not only prevented all the periodic symptoms but also relieved their diplopia, which had been present between attacks.

Behçet's disease in patients of west African and Afro-Caribbean origin.

AIM: To report the presence of Behçet's disease with ocular involvement in patients of west African or Afro-Caribbean origin. METHODS: Case series of eight patients reporting to a tertiary uveitis service. RESULTS: Eight patients with typical features of the disease are presented. Six of the eight patients were tested and found to be HLA-B51 negative. CONCLUSION: Behçet's disease has only been reported in sporadic case reports in the indigenous west African and Afro-Caribbean populations, in whom the incidence of HLA B51 is also very low. A series of patients from the London region presented with the typical symptoms and signs of disease, most of whom were also HLA B51 negative. The presence of disease in this population, when absent in the indigenous population, suggests either that ascertainment of disease is poor in the indigenous population or that acquired factors may be important in the aetiology of the disease.