Association between morbidity among term newborns and low-risk caesarean delivery rates.

OBJECTIVE: To examine the association between county-level caesarean delivery (CD) rates among women at low risk and morbidity among term newborns. DESIGN: Cross-sectional study. SETTING: Population-based study of US county-level birth data from 2015 to 2017. POPULATION: Nulliparous women with term, singleton, vertex-presenting infants (NTSV) at low risk for morbidity. METHODS: The primary exposure was county-level CD rates. MAIN OUTCOME MEASURES: The outcome was morbidity among the low-risk NTSV cohort, categorised as severe (5-minute Apgar score of ≤3, assisted ventilation for ≥6 hours, severe neurologic injury or seizure, transfer or death) or moderate (5-minute Apgar score of <7 but >3, administration of antibiotics or assisted ventilation at delivery). We used linear regression models to determine the association between county NTSV CD and neonatal morbidity rates with cluster robust standard errors. RESULTS: The analysis included data from 2 753 522 births in 952 counties from all 48 states. The mean NTSV CD rate was 23.6% (standard deviation 4.8%). The median severe and moderate neonatal morbidity rates were 15.2 (interquartile range, IQR 9.4-23.6) and 52.5 (IQR 33.4-75.7) per 1000 births, respectively. In the unadjusted analysis using the risk-adjusted exposure and outcome, every percentage point increase in the CD rate of a county was associated with 0.6 (95% CI -0.9, -0.3) and 2.3 fewer (95% CI -3.4, -1.1) cases of severe and moderate neonatal morbidity per 1000 live births. After adjustment for other county factors, the relationships remained significant. These findings were tested in multiple sensitivity analyses. CONCLUSIONS: Lower county-level NTSV CD rates were associated with a small increase in morbidity among term newborns in the USA. TWEETABLE ABSTRACT: Lower county-level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA.

Hospital volume and cesarean delivery among low-risk women in a nationwide sample.

OBJECTIVE: We sought to determine if hospital delivery volume was associated with a patient's risk for cesarean delivery in low-risk women. STUDY DESIGN: This study retrospectively examines a cohort of 1 657 495 deliveries identified in the 2013 Nationwide Readmissions Database. Hospitals were stratified by delivery volume quartiles. Low-risk patients were identified using the Society for Maternal-Fetal Medicine definition (n=845 056). A multivariable logistic regression accounting for hospital-level clustering was constructed to assess the factors affecting a patient's odds for cesarean delivery. RESULTS: The range of cesarean delivery rates was 2.4-51.2% among low-risk patients, and the median was 16.5% (IQR 12.8-20.5%). The cesarean delivery rate was higher in the top two-volume-quartile hospitals (17.4 and 18.2%) compared to the bottom quartiles (16.4 and 16.3%) (P<0.001). Hospital volume was not associated with a patient's odds for cesarean delivery after adjusting for patient and other hospital characteristics (P=0.188). CONCLUSION: Hospital delivery volume is not an independent predictor of cesarean delivery in this population.

Toxoplasma gondii seroprevalence and association with equine protozoal myeloencephalitis: A case-control study of Californian horses.

While toxoplasmosis is not commonly considered a clinical disease of equines, previous seroprevalence studies have reported differing background rates of Toxoplasma gondii infection in horses globally. The objective of this study was to evaluate possible associations between T. gondii seroprevalence and clinical signs of equine protozoal myeloencephalitis (EPM) in horses. Using a case-control study design, 720 Californian horses with neurologic signs compatible with EPM were compared to healthy, non-neurologic horses for the presence of T. gondii antibodies (using indirect fluorescent antibody tests [IFAT]). Toxoplasma gondii seroprevalence among cases and controls was determined at standard serum cut-offs: 40, 80, 160, 320, and 640. At a T. gondii titre cut-off of 320, horses with clinical signs compatible with EPM had 3.55 times the odds of a seropositive test compared to those without clinical signs (P<0.01) when adjusted for covariates. When restricted to the autumn season and at the same titre cut-off, an EPM suspect horse had 6.4 times the odds of testing seropositive to T. gondii, compared to non-neurologic horses. The association between high T. gondii titres and clinical signs compatible with EPM is potentially reflective of toxoplasmosis in equines. Serologic testing of cerebrospinal fluid and isolation of T. gondii in EPM suspect cases should be considered. Future studies investigating the relationship between T. gondii and EPM are warranted.

The role of patients and providers in the timing of follow-up visits. Telephone Care Study Group.

OBJECTIVE: Although the decision about how frequently to see outpatients has a direct impact on a provider's workload and may impact health care costs, revisit intervals have rarely been a topic of investigation. To begin to understand what factors are correlated with this decision, we examined baseline data from a Department of Veterans Affairs (VA) Cooperative Study designed to evaluate telephone care. DESIGN: Observational study based on extensive patient data collected during enrollment into the randomized trial. Providers were required to recommend a revisit interval (e.g., "return visit in 3 months") for each patient before randomization, under the assumption that the patient would be receiving clinic visits as usual. POPULATION/SETTING: Five hundred seventy-one patients over age 55 cared for by one of the 30 providers working in three VA general medical clinics. Patients for whom immediate follow-up (

Impact of gowning on visit length and physical examinations.

We evaluated the effect of a randomized trial of gowning on length of visit and number of physical examinations performed in an outpatient clinic. Nineteen senior internal medicine trainees saw 110 patients without gowns and 113 patients with gowns. Patients without gowns were with the trainees 25.2 +/- 11.9 (mean +/- SD) minutes versus 24.2 +/- 10.3 minutes for gowned patients (p = .51). Ungowned patients were in the examination room a total of 38.5 +/- 15.9 minutes versus 42.9 +/- 17.6 minutes for gowned patients (p = .06). The number of patients that underwent physical examinations was the same (89) for gowned and ungowned groups, and the distribution of the number of examinations by patient group differed only slightly (p = .88). Gowning did not significantly decrease the length of visit or increase the number of physical examinations performed.

Health services clinical trials: design, conduct, and cost methodology.

Randomized clinical trials and their developing methodology have had substantial impact on the advancement of medical practice. With the emergence of managed care and increased emphasis on the reduction of medical care expenditures, cost evaluation is now becoming a part of clinical trial research. The papers by Henderson et al. and Manheim that follow address the evolution of health services research, its application to multicenter clinical trials in a major U.S. health-care system, and methods of assessing costs in health services clinical trials.

Bladder washing cytology. Comparison of two analytic methods and two proposed quantitative criteria for carcinoma in situ.

OBJECTIVE: To compare bladder washing cytology preparations created by the Nucleopore filter and slide centrifuge techniques and to evaluate a marker for carcinoma in situ (CIS). STUDY DESIGN: Nucleopore filter and slide centrifuge preparations from 27 patients with urothelial carcinoma were compared and used to create two criteria for CIS. To study reproducibility, three observers evaluated 25 filter preparations for these CIS criteria. RESULTS: The filter technique displayed more better-preserved single cancer cells (P = .02) and a higher percent group count (the number of cancer cell groups divided by the sum of the number of single cancer cells plus the number of cancer cell groups) (P = .005) than did the cytocentrifuge technique. The initial study showed that patients with many single tumor cells and lower percent group counts were more likely to have CIS than patients without this combined condition (P = .001). This CIS marker had moderate reproducibility (kappa = 0.47 +/- 0.12). CONCLUSION: The filter technique had better cellular recovery and preservation of tumor cells than did the centrifuge technique. Quantitative cytologic criteria proposed in this study may be an indication that CIS may be present; improved sensitivity and specificity may be obtained if they are combined with other criteria.

An index for assessing blindness in a multi-centre clinical trial: disulfiram for alcohol cessation--a VA cooperative study.

This paper considers an index to assess the success of blinding with application to a clinical trial of disulfiram. The index increases as the success of blinding increases, accounts for uncertain responses, and is scaled to an interval of 0.0 to 1.0, 0.0 being complete lack of blinding and 1.0 being complete blinding.

Silent cerebral infarction in patients with nonrheumatic atrial fibrillation. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.

BACKGROUND: Cerebral infarction in patients with atrial fibrillation may vary from being clinically silent to catastrophic. The prevalence of silent cerebral infarction and its effect as a risk factor for symptomatic stroke are important considerations for the evaluation of patients with atrial fibrillation. METHODS AND RESULTS: This Veterans Affairs cooperative study was a double-blind controlled trial designed primarily to determine the efficacy of warfarin for the prevention of stroke in neurologically normal patients with nonrheumatic atrial fibrillation. It also was designed to evaluate patients with silent cerebral infarction. Computed tomography scans of the head were performed at entry, at the time of any subsequent stroke, and at termination of follow-up on all patients who completed the study without a neurological event. Of 516 evaluable scans performed at entry, 76 (14.7%) had evidence of one or more silent cerebral infarcts. Age (P = .011), a history of hypertension (P = .003), active angina (P = .012), and elevated mean systolic blood pressure (P < .001) were associated with the presence of this finding. Silent cerebral infarction occurred during the study at rates of 1.01% and 1.57% per year for the placebo and warfarin treatment groups, respectively (NS). Silent cerebral infarction at entry was not an independent predictor of later symptomatic stroke, but active angina was a significant predictor; 15% of the placebo-assigned patients with angina developed a stroke compared with 5% of the placebo-assigned patients without angina. CONCLUSIONS: Silent cerebral infarction is frequently seen in asymptomatic patients with atrial fibrillation. Age, history of hypertension, active angina, and elevated mean systolic blood pressure were associated with silent infarction at entry. The sample size was too small to determine whether warfarin had an effect on the incidence of silent infarction during the trial. Active angina at baseline was the only significant independent predictor for the later development of symptomatic stroke.

Role of transesophageal echocardiography in the detection of left atrial thrombus in patients with chronic nonrheumatic atrial fibrillation.

Transesophageal echocardiography was used to assess cardiac abnormalities associated with embolization in patients who had completed the Department of Veterans Affairs Cooperative Study of Stroke Prevention in Nonrheumatic Atrial Fibrillation at the Minneapolis and West Haven Department of Veterans Affairs Medical Centers without an embolic event. Patients were men, 71 +/- 7 years old, with atrial fibrillation of 6.2 +/- 4.3 years' duration who had received warfarin (n = 32) or placebo (n = 23) for 2 years. Thrombi were found in 5 of 55 patients (warfarin 4 and placebo 1; p = 0.39); spontaneous echo contrast was seen in 4 of 5 patients. Other abnormalities identified included spontaneous echo contrast (47%), patent foramen ovale (54%), atrial septal aneurysm (7.3%), and left ventricular thrombus (3.6%). During 34 months of posttreatment follow-up, 5 patients had a stroke (1 fatal), and 10 died. Potential sources of emboli did not predict subsequent outcome. Thus warfarin therapy did not preclude the presence of thrombi. Stroke reduction likely involves the prevention of emboli from sources in addition to the atrial appendage.

Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.

BACKGROUND: Nonrheumatic atrial fibrillation is common among the elderly and is associated with an increased risk of stroke. We investigated whether anticoagulation with warfarin would reduce this risk. METHODS: We conducted a randomized, double-blind, placebo-controlled study to evaluate low-intensity anticoagulation with warfarin (prothrombin-time ratio, 1.2 to 1.5) in 571 men with chronic nonrheumatic atrial fibrillation; 525 patients had not previously had a cerebral infarction, whereas 46 patients had previously had such an event. The primary end point was cerebral infarction; secondary end points were cerebral hemorrhage and death. RESULTS: Among the patients with no history of stroke, cerebral infarction occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years (4.3 percent per year) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years (0.9 percent per year). The reduction in risk with warfarin therapy was 0.79 (95 percent confidence interval, 0.52 to 0.90; P = 0.001). The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group (risk reduction, 0.79; P = 0.02). The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group. Other major hemorrhages, all gastrointestinal, occurred in 10 patients: 4 in the placebo group, for a rate of 0.9 percent per year, and 6 in the warfarin group, for a rate of 1.3 percent per year. There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group (risk reduction, 0.31; P = 0.19). Cerebral infarction was more common among patients with a history of cerebral infarction (9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group) than among those without such a history. CONCLUSIONS: Low-intensity anticoagulation with warfarin prevented cerebral infarction in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage. This benefit extended to patients over 70 years of age.

Residual analgesic effects of morphine in 55 four-period crossover analgesic studies.

Subjective response data from 55 postoperative pain studies were examined for the residual analgesic effects of morphine. The studies were planned as four-period crossover designs for four treatments. Each patient received 5 and 10 mg of morphine and two doses of a test preparation. Two measures of analgesia were used: Sum of the Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR). To facilitate analysis, two two-period groups were defined. Morphine data for periods 1 and 2 were designated as group A, and morphine data for periods 3 and 4 were designated as group B. Residual analgesic effects were 0.12 for both SPID and TOTPAR in group A and were 0.65 and 0.17 for SPID and TOTPAR, respectively, in group B. In these 55 studies, there was no evidence of significant residual analgesic effects. Thus the crossover design is an appropriate method for the evaluation of selected parenteral analgesics in the postoperative pain model.

A randomized trial of acetohydroxamic acid for the treatment and prevention of infection-induced urinary stones in spinal cord injury patients.

Acetohydroxamic acid is known to inhibit bacterial urease activity, thus, reducing urinary ammonia levels. A double-blind placebo-controlled clinical trial of acetohydroxamic acid was conducted at 12 Veterans Administration spinal cord injury units. A total of 210 male spinal cord injury patients with chronic urea-splitting urinary infection was enrolled for a scheduled followup of 2 years. The study data support the usefulness of acetohydroxamic acid in reducing urinary ammonia. At every followup visit the acetohydroxamic acid patients with stones had decreases in ammonia of 30 to 48 mg. per dh., while the placebo patients had increases in ammonia. Acetohydroxamic acid also retarded stone growth. Patients with stones treated with acetohydroxamic acid exhibited significantly longer intervals from randomization to first stone growth than patients treated with placebo (p less than 0.005, medians 15 versus 9 months). Acetohydroxamic acid reduced significantly the proportion of patients with stone growth at 12 months (33 versus 60 per cent, p equals 0.017). This decrease was diminished at 24 months (42 versus 60 per cent, p equals 0.260). Patient attrition was 31 per cent in the placebo group and 62 per cent in the acetohydroxamic acid group, the latter attrition being primarily owing to patient request because of mild symptoms. Of the acetohydroxamic acid and placebo patients 62 and 29 per cent, respectively, reported drug side effects but all were reversible and no unanticipated or life-threatening reactions occurred.

Disulfiram treatment of alcoholism. A Veterans Administration cooperative study.

We conducted a controlled, blinded, multicenter study of disulfiram treatment of alcoholism in 605 men randomly assigned to 250 mg of disulfiram (202 men); 1 mg of disulfiram (204 men), a control for the threat of the disulfiram-ethanol reaction; or no disulfiram (199 men), a control for the counseling that all received. Bimonthly treatment assessments were done for one year. Relative/friend interviews and blood and urine ethanol analyses were used to corroborate patients' reports. There were no significant differences among the groups in total abstinence, time to first drink, employment, or social stability. Among the patients who drank and had a complete set of assessment interviews, those in the 250-mg disulfiram group reported significantly fewer drinking days (49.0 +/- 8.4) than those in the 1-mg (75.4 +/- 11.9) or the no-disulfiram (86.5 +/- 13.6) groups. There was a significant relationship between adherence to drug regimen and complete abstinence in all groups. We conclude that disulfiram may help reduce drinking frequency after relapse, but does not enhance counseling in aiding alcoholic patients to sustain continuous abstinence or delay the resumption of drinking.

Crossover and noncrossover designs in four-point parallel line analgesic assays.

Fifty-nine analgesic investigations designed as four-point parallel line crossover assays were examined. Sum of pain intensity differences (SPID) and total pain relief (TOTPAR) were the subjective response measures. Separate analyses with four-point crossover data and first-dose data (noncrossover) allowed comparison within each study of these two approaches. The crossover analysis allows for removal of the subject component of variance, which in these studies was a substantial fraction of the error variance (0.49 for SPID; 0.56 for TOTPAR). For this type of study, 2.4 times as many subjects would have to be recruited in a noncrossover design to obtain precision equivalent to that of the crossover design. Thus efficiency considerations argue for the crossover design in cases in which a treatment carryover effect may be assumed to be negligible.

A model for the development, conduct, and monitoring of multicenter clinical trials in the Veterans Administration.

In the past 20-30 years, increased interest on the part of biostatisticians and medical investigators has been exhibited in clinical trial research. In the mid-1940's, the Veterans Administration Hospital system was recognized as an ideal environment for the conduct of multicenter clinical trials, with the initiation of a study to determine the effectiveness of chemotherapy in the treatment of tuberculosis, in a joint effort with the United States Armed Forces. This research effort later evolved into what is presently known as the Cooperative Studies Program of the Medical Research Service. Within the past seven years, this program has undergone considerable growth and reorganization. This paper describes a system for the review, operation, and conduct of multicenter clinical research in a wide variety of medical specialty areas. In particular, it stresses the importance of core biostatistical coordinating centres where biostatisticians and other key support personnel constitute an integral part of the planning and development, implementation, conduct, and reporting of many cooperative studies in diverse disciplines. The paper also describes the interaction of various review bodies and a check and balance system to promote sound management and opportunity for the exchange of clinical and biostatistical methodology in the cooperative study setting.