The next 'pandemic playbook' needs to prioritize the needs of children-and a clear roadmap for opening schools.

The national influenza pandemic response plan includes short-term school closures as an infection mitigation measure, based on modeling data regarding the role of pediatric populations and schools as drivers of disease spread. Modeled estimates regarding the role of children and their in-school contacts as drivers of community transmission of endemic respiratory viruses were used in part to justify prolonged school closures throughout the United States. However, disease transmission models extrapolated from endemic pathogens to novel ones may underestimate the degree to which spread is driven by population immunity and overestimate the impact of school closures as a means of reducing child contacts, particularly in the longer-term. These errors, in turn, may have caused incorrect estimations about the potential benefits of closing schools on a society level while simultaneously failing to account for the significant harms of long-term educational disruption. Pandemic response plans need to be updated to include nuances regarding drivers of transmission such as pathogen type, population immunity, and contact patterns, and disease severity in different groups. Expected duration of impact also needs to be considered, recognizing that effectiveness of different interventions, particularly those focused on limiting social interactions, are short-lived. Additionally, future iterations should include risk-benefit assessments. Interventions that are particularly harmful to certain groups, such as school closures are on children, should be de-emphasized and time limited. Finally, pandemic responses should include ongoing and continuous policy re-evaluation and should include a clear plan for de-implementation and de-escalation.

Lack of Association Between Pandemic School Mode Policy and Pediatric Body Mass Index Percentile Over Time.

During the 2020-2021 academic year, schools across the country were closed for prolonged periods. Prior research suggests that children tend to gain more weight during times of extended school closures, such as summer vacation; however, little is known about the impact of school learning mode on changes. Thus, the aim of this study was to measure the association between school mode (in-person, hybrid, remote) and pediatric body mass index (BMI) percentile increases over time. In this longitudinal, statewide retrospective cohort study in Massachusetts, we found that BMI percentile increased in elementary and middle school students in all learning modes, and that increases slowed but did not reverse following the statewide reopening. Body mass percentile increases were highest in elementary school aged children. Hispanic ethnicity and receipt of Medicaid insurance were also associated with increases. Additional research is needed to identify strategies to combat pediatric body mass percentile increases and to address disparities.

A novel household-based patient outreach pilot program to boost late-season influenza vaccination rates during the COVID-19 pandemic.

BACKGROUND: The objective of this study was to test a novel household-based approach to improve late-season influenza vaccine uptake during the 2020-2021 season, using Epic's MyChart patient portal messages and/or interactive voice response telephone calls. METHODS: This study was a non-blinded, quality improvement program using a block randomized design conducted among patients from Reliant Medical Group clinics residing in a traditional household (≥2 individuals clinically active in the Reliant system living at the same address). Households were randomized 1:1:1 into intervention arms: non-tailored communication (messaging based on CDC's seasonal influenza vaccination campaign), tailored communication (comprehensive communication including reinforcement of the importance of influenza vaccination for high-risk individuals), and standard-of-care control. Influenza vaccination during the program was captured via medical records, and the odds of vaccination among communication arms versus the control arm were assessed. A survey assessing influenza vaccination drivers was administered using MyChart. RESULTS: Influenza vaccination increased by 3.3% during the program period, and no significant differences in vaccination were observed in intervention arms relative to the control arm. Study operationalization faced substantial challenges related to the concurrent COVID-19 pandemic. Compared with vaccinated survey respondents, unvaccinated respondents less frequently reported receiving a recommendation for influenza vaccination from their healthcare provider (15.8% vs. 42.3%, p < 0.001) or awareness that vaccination could protect themselves and higher risk contacts (82.3% vs. 92.6%, p < 0.001). CONCLUSIONS: No significant effects of the interventions were observed. Survey results highlighted the importance of healthcare provider recommendations and the need for increased education around the benefits of vaccination.

Clinician perspectives on pediatric COVID-19 vaccination: A qualitative study in central and western, Massachusetts.

We explored perspectives of clinicians in central and western Massachusetts about efforts to vaccinate pediatric patients against COVID-19 as well as best practices and challenges for vaccine delivery. We conducted semi-structured qualitative interviews (n = 16) with family practice and pediatric clinicians between late October and early December 2021. Our interviews addressed: process for vaccination and vaccine promotion, parental receptivity to COVID-19 vaccination, receptivity to other pediatric vaccines, resources needed to support vaccine promotion, and best practices developed to encourage hesitant parents. Using a multi-prong recruitment strategy we invited clinicians to participate in telephone interviews, which were audio-recorded and transcribed. We used rapid qualitative analysis to produce summary templates for each interview which were ultimately combined into a matrix summary. The majority of participants (n = 10) were offering the vaccine in their own clinics, while the remainder cited challenges related to staffing, logistics, and space that prevented them from offering the vaccine. Clinicians reported parents fall into three groups: vaccine-accepting, hesitant but potentially accepting, and refusers. Strategies they identified that worked to encourage hesitant parents were sharing personal vaccine stories, acknowledging parents' fears about the vaccine, and being persistent with the most hesitant parents. Yet resources are needed including educational materials and training in how to have these conversations. While challenges related to staffing and space will be difficult to overcome for clinics to be able to offer vaccination on-site, our results highlight the importance of developing effective messaging strategies and training clinicians in how to integrate them into routine practice.

Inequities in coronavirus disease 2019 (COVID-19) Vaccination Rates Among Adolescents in Massachusetts: A Cross-sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected more socioeconomically disadvantaged persons and areas. We sought to determine how certain sociodemographic factors were correlated to adolescents' COVID-19 vaccination rates in towns and cities ("communities") in the Commonwealth of Massachusetts. METHODS: Data on COVID-19 vaccination rates were obtained over a 20-week period from 30 March 2021 to 10 August 2021. Communities' adolescent (ages 12-19) vaccination rates were compared across quintiles of community-level income, COVID-19 case rate, and proportion of non-Hispanic Black or Hispanic individuals. Other variables included population density and earlier COVID-19 vaccination rates of adolescents and adults, averaged from 30 March to 11 May to determine their effects on vaccination rates on 10 August. Linear and logistic regression was used to estimate individual effects of variables on adolescent vaccination rates. RESULTS: Higher median household income, lower proportion of Black or Hispanic individuals, higher early adolescent COVID-19 vaccination rates, and higher early adult COVID-19 vaccination rates were associated with higher later adolescent COVID-19 vaccination rates. Income per $10 000 (adjusted odds ratio [aOR] = 1.01 [95% confidence interval [CI] = 1.01-1.02]), proportion of Hispanic individuals (aOR = 1.33 [95% CI: 1.13-1.56]), early adolescent COVID-19 vaccination rates (aOR = 5.28 [95% CI: 4.67-5.96]), and early adult COVID-19 vaccination rates (aOR = 2.31 [95% CI: 2.02-2.64]) were associated with higher adolescent COVID-19 vaccination on 10 August, whereas proportion of Black individuals approached significance (aOR = 1.26 [95% CI: .98-1.61]). CONCLUSIONS: Vaccination efforts for adolescents in Massachusetts should focus on boosting vaccination rates early in communities with the lowest incomes and greatest proportion of Hispanic individuals and consider targeting communities with a greater proportion of Black individuals.

Electronic Health Record Portal Messages and Interactive Voice Response Calls to Improve Rates of Early Season Influenza Vaccination: Randomized Controlled Trial.

BACKGROUND: Patient reminders for influenza vaccination, delivered via an electronic health record patient portal and interactive voice response calls, offer an innovative approach to engaging patients and improving patient care. OBJECTIVE: The goal of this study was to test the effectiveness of portal and interactive voice response outreach in improving rates of influenza vaccination by targeting patients in early September, shortly after vaccinations became available. METHODS: Using electronic health record portal messages and interactive voice response calls promoting influenza vaccination, outreach was conducted in September 2015. Participants included adult patients within a large multispecialty group practice in central Massachusetts. Our main outcome was electronic health record-documented early influenza vaccination during the 2015-2016 influenza season, measured in November 2015. We randomly assigned all active portal users to 1 of 2 groups: (1) receiving a portal message promoting influenza vaccinations, listing upcoming clinics, and offering online scheduling of vaccination appointments (n=19,506) or (2) receiving usual care (n=19,505). We randomly assigned all portal nonusers to 1 of 2 groups: (1) receiving interactive voice response call (n=15,000) or (2) receiving usual care (n=43,596). The intervention also solicited patient self-reports on influenza vaccinations completed outside the clinic. Self-reported influenza vaccination data were uploaded into the electronic health records to increase the accuracy of existing provider-directed electronic health record clinical decision support (vaccination alerts) but were excluded from main analyses. RESULTS: Among portal users, 28.4% (5549/19,506) of those randomized to receive messages and 27.1% (5294/19,505) of the usual care group had influenza vaccinations documented by November 2015 (P=.004). In multivariate analysis of portal users, message recipients were slightly more likely to have documented vaccinations when compared to the usual care group (OR 1.07, 95% CI 1.02-1.12). Among portal nonusers, 8.4% (1262/15,000) of those randomized to receive calls and 8.2% (3586/43,596) of usual care had documented vaccinations (P=.47), and multivariate analysis showed nonsignificant differences. Over half of portal messages sent were opened (10,112/19,479; 51.9%), and over half of interactive voice response calls placed (7599/14,984; 50.7%) reached their intended target, thus we attained similar levels of exposure to the messaging for both interventions. Among portal message recipients, 25.4% of message openers (2570/10,112) responded to a subsequent question on receipt of influenza vaccination; among interactive voice response recipients, 72.5% of those reached (5513/7599) responded to a similar question. CONCLUSIONS: Portal message outreach to a general primary care population achieved a small but statistically significant improvement in rates of influenza vaccination (OR 1.07, 95% CI 1.02-1.12). Interactive voice response calls did not significantly improve vaccination rates among portal nonusers (OR 1.03, 95% CI 0.96-1.10). Rates of patient engagement with both modalities were favorable. TRIAL REGISTRATION: ClinicalTrials.gov NCT02266277; https://clinicaltrials.gov/ct2/show/NCT02266277.

A pyrene-based two-photon excitable fluorescent probe to visualize nuclei in live cells.

The two-photon absorption properties of a pyrene-pyridinium dye (1) were studied for potential application in two-photon spectroscopy. When probe 1 was used in cellular two-photon fluorescence microscopy imaging, it allowed the visualization of nuclei in live cells with a relatively low probe concentration (such as 1 µM). Spectroscopic evidence further revealed that probe 1 interacted with DNA as an intercalator. The proposed DNA intercalation properties of probe 1 were consistent with the experimental findings that suggested that the observed nucleus staining ability is dependent on the substituents on the pyridinium fragment of the probe.

Improving Rates of Outpatient Influenza Vaccination Through EHR Portal Messages and Interactive Automated Calls: A Randomized Controlled Trial.

BACKGROUND: Patient reminders for influenza vaccination, delivered via electronic health record (EHR) patient portal messages and interactive voice response (IVR) calls, offer an innovative approach to improving patient care. OBJECTIVE: To test the effectiveness of portal and IVR outreach in improving rates of influenza vaccination. DESIGN: Randomized controlled trial of EHR portal messages and IVR calls promoting influenza vaccination. PARTICIPANTS: Adults with no documented influenza vaccination 2 months after the start of influenza season (2014-2015). INTERVENTION: Using a factorial design, we assigned 20,000 patients who were active portal users to one of four study arms: (a) receipt of a portal message promoting influenza vaccines, (b) receipt of IVR call with similar content, (c) both a and b, or (d) neither (usual care). We randomized 10,000 non-portal users to receipt of IVR call or usual care. In all intervention arms, information on pneumococcal vaccination was included if the targeted patient was overdue for pneumococcal vaccine. MAIN MEASURES: EHR-documented influenza vaccination during the 2014-2015 influenza season, measured April 2015. KEY RESULTS: Among portal users, 14.0% (702) of those receiving both portal messages and calls, 13.4% (669) of message recipients, 12.8% (642) of call recipients, and 11.6% (582) of those with usual care received vaccines. On multivariable analysis of portal users, those receiving portal messages alone (OR 1.20, 95% CI 1.06-1.35) or IVR calls alone (OR 1.15 95% CI 1.02-1.30) were more likely than usual care recipients to be vaccinated. Those receiving both messages and calls were also more likely than the usual care group to be vaccinated (ad hoc analysis, using a Bonferroni correction: OR 1.29, 97.5% CI 1.13, 1.48). Among non-portal users, 8.5% of call recipients and 8.6% of usual care recipients received influenza vaccines (p = NS). Pneumococcal vaccination rates showed no significant improvement. CONCLUSIONS: Our outreach achieved a small but significant improvement in influenza vaccination rates. Registration: ClinicalTrials.gov Identifier NCT02266277 ( https://clinicaltrials.gov/ct2/show/NCT02266277 ).

Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the PROFILE Trial After 24 Years.

OBJECTIVES: The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND: Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use. METHODS: Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction ≤35% to receive long-term treatment with placebo or flosequinan (75 or 100 mg/day) in addition to their usual therapy. The primary outcome was all-cause mortality. RESULTS: The trial was terminated after a recommendation of the Data and Safety Monitoring Board, because during an average of 10 months of follow-up, 192 patients died in the placebo group and 255 patients died in the flosequinan group (hazard ratio: 1.39, 95% confidence interval: 1.15 to 1.67; p = 0.0006). Flosequinan also increased the risk of disease progression, which was paralleled by drug-related increases in heart rate and neurohormonal activation. However, during the first month, patients in the flosequinan group were more likely to report an improvement in well-being and less likely to experience worsening heart failure. Similarly, during the month following drug withdrawal at the end of the trial, patients withdrawn from flosequinan were more likely than those withdrawn from placebo to report symptoms of or to require treatment for worsening heart failure. CONCLUSIONS: Although flosequinan produced meaningful symptomatic benefits during short- and long-term treatment, the drug increased the risk of death in patients with severe chronic heart failure.

Improving Rates of Influenza Vaccination Through Electronic Health Record Portal Messages, Interactive Voice Recognition Calls and Patient-Enabled Electronic Health Record Updates: Protocol for a Randomized Controlled Trial.

BACKGROUND: Clinical decision support (CDS), including computerized reminders for providers and patients, can improve health outcomes. CDS promoting influenza vaccination, delivered directly to patients via an electronic health record (EHR) patient portal and interactive voice recognition (IVR) calls, offers an innovative approach to improving patient care. OBJECTIVE: To test the effectiveness of an EHR patient portal and IVR outreach to improve rates of influenza vaccination in a large multispecialty group practice in central Massachusetts. METHODS: We describe a nonblinded, randomized controlled trial of EHR patient portal messages and IVR calls designed to promote influenza vaccination. In our preparatory phase, we conducted qualitative interviews with patients, providers, and staff to inform development of EHR portal messages with embedded questionnaires and IVR call scripts. We also provided practice-wide education on influenza vaccines to all physicians and staff members, including information on existing vaccine-specific EHR CDS. Outreach will target adult patients who remain unvaccinated for more than 2 months after the start of the influenza season. Using computer-generated randomization and a factorial design, we will assign 20,000 patients who are active users of electronic patient portals to one of the 4 study arms: (1) receipt of a portal message promoting influenza vaccines and offering online appointment scheduling; (2) receipt of an IVR call with similar content but without appointment facilitation; (3) both (1) and (2); or (4) neither (1) nor (2) (usual care). We will randomize patients without electronic portals (10,000 patients) to (1) receipt of IVR call or (2) usual care. Both portal messages and IVR calls promote influenza vaccine completion. Our primary outcome is percentage of eligible patients with influenza vaccines administered at our group practice during the 2014-15 influenza season. Both outreach methods also solicit patient self-report on influenza vaccinations completed outside the clinic or on barriers to influenza vaccination. Self-reported data from both outreach modes will be uploaded into the EHR to increase accuracy of existing provider-directed EHR CDS (vaccine alerts). RESULTS: With our proposed sample size and using a factorial design, power calculations using baseline vaccination rate estimates indicated that 4286 participants per arm would give 80% power to detect a 3% improvement in influenza vaccination rates between groups (α=.05; 2-sided). Intention-to-treat unadjusted chi-square analyses will be performed to assess the impact of portal messages, either alone or in combination with the IVR call, on influenza vaccination rates. The project was funded in January 2014. Patient enrollment for the project described here completed in December 2014. Data analysis is currently under way and first results are expected to be submitted for publication in 2016. CONCLUSIONS: If successful, this study's intervention may be adapted by other large health care organizations to increase vaccination rates among their eligible patients. CLINICALTRIAL: ClinicalTrials.gov NCT02266277; https://clinicaltrials.gov/ct2/show/NCT02266277 (Archived by WebCite at http://www.webcitation.org/6fbLviHLH).

Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure.

BACKGROUND: This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF). METHODS: We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization. RESULTS: In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29). CONCLUSIONS: In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425).

Statistical consideration of the strategy for demonstrating clinical evidence of effectiveness--one larger vs two smaller pivotal studies.

As a regulatory strategy, it is nowadays not uncommon to conduct one confirmatory pivotal clinical trial, instead of two, to demonstrate efficacy and safety in drug development. This paper is intended to investigate the statistical foundation of such an approach. The one-study approach is compared with the conventional two-study approach in terms of power, type-I error, and fundamental statistical assumptions. Necessary requirements for a single-study model is provided in order to maintain equivalent evidence as that from a two-study model. In general, one-study model is valid only under a 'one population' assumption. In addition, higher data quality and more convincing and robust results need to be demonstrated in such cases. However, when 'one-population' assumption is valid and appropriate methods are selected, a one-study model can have a better power using the same sample size. The paper also investigates statistical assumptions and methods for making an overall inference when a two-study model has been used. The methods for integrated analysis are evaluated. It is important for statisticians to select correct pooling strategy based on the project objective and statistical hypothesis.

Can the diagnosis of pelvic inflammatory disease be excluded without a bimanual examination?

Now that urine-based tests are available for detection of Chlamydia and gonorrhea, we sought to determine whether history alone could be used to exclude pelvic inflammatory disease (PID) and thus preclude a bimanual examination. The study design was a retrospective chart review. The study population included females aged 15-24 years diagnosed with PID. Outcome measures were documentation of screening symptoms (abdominal pain, dyspareunia, or abnormal vaginal bleeding) in the medical record. Our primary analysis was sensitivity of screening symptoms for identifying patients with PID. At least 1 of the 3 screening symptoms was reported by 93% of the PID group. If absence of all 3 screening symptoms were used as a screening instrument to exclude a bimanual examination, many women with lower genital tract symptoms could be evaluated noninvasively. However, this approach could result in delayed diagnosis of PID in a small number of patients. Before this strategy is adopted, a large prospective study is needed.

Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Neurohormones are considered markers of heart failure progression. We examined whether changes in brain natriuretic peptide (BNP) and norepinephrine (NE) over time are associated with corresponding changes in mortality and morbidity in the Valsartan Heart Failure Trial. METHODS AND RESULTS: Plasma BNP and NE were measured before randomization and during follow-up in approximately 4300 patients in the Valsartan Heart Failure Trial. The relation between baseline BNP and NE and all-cause mortality and first morbid event (M&M) was analyzed in subgroups, with values above and below the median, and by quartiles. The change and percent change from baseline to 4 and 12 months in BNP and NE were also analyzed by quartiles for subsequent M&M. Risk ratios for M&M were calculated using a Cox proportional hazard model. Risk ratio of M&M for patients with baseline BNP or NE above the median was significantly higher than that for patients with values below the median. Baseline BNP and NE in quartiles also showed a quartile-dependent increase in M&M. BNP had a stronger association with M&M than NE. Patients with the greatest percent decrease in BNP and NE from baseline to 4 and 12 months had the lowest whereas patients with greatest percent increase in BNP and NE had the highest M&M. CONCLUSIONS: Not only are plasma BNP and NE important predictors of heart failure M&M, but changes in these neurohormones over time are associated with corresponding changes in M&M. These data further reinforce their role as significant surrogate markers in HF and underscore the importance of including their measurement in HF trials.

Internal thoracic artery grafts for the entire heart at a mean of 12 years.

BACKGROUND: There is consensus today that the long-term results of bypassing the left anterior descending artery with an internal thoracic artery (ITA) graft are superior to those of a saphenous vein graft. Our hypothesis for this study was that three-vessel revascularization with only ITA grafts would also give excellent results. METHODS: Using our previously described techniques to enhance the length of ITA grafts by skeletonization and high mediastinal mobilization, we were able to perform tension-free, three-vessel revascularization using only ITA grafts in 125 (83%) of a consecutive series of 150 patients with three-vessel occlusive coronary disease. We followed 100% of these 125 exclusive ITA graft patients (average of 3.9 anastomoses per patient) to their time of death (59; 47.2%) or current living status (66; 52.8%). RESULTS: Combined intraoperative graft flows averaged 225 mL/min. Of the 125 patients in this study (average age, 63.5 years), 121 (96.8%) lived beyond 40 days. Of these 121 patients, 55 (45%) died at a mean of 7 years postoperatively and 66 (55%) are still living at a mean of 12.1 years. Of these 121 patients, 112 (93%) had angina at baseline. Of these 112, 92 (85%) were angina free at a mean of 9.1 years postoperatively. Freedom from infarction was 100% at 5 years and 97% at 10 years. Freedom from reintervention was 90% at a mean of 9.8 years. CONCLUSIONS: Use of ITA grafts for three-vessel coronary revascularization provides excellent results and is both practical and appropriate for many patients.

Self-designing two-stage trials to minimize expected costs.

In the design of clinical trials, the sample size for the trial is traditionally calculated from estimates of parameters of interest, such as the mean treatment effect, which can often be inaccurate. However, recalculation of the sample size based on an estimate of the parameter of interest that uses accumulating data from the trial can lead to inflation of the overall Type I error rate of the trial. The self-designing method of Fisher, also known as the variance-spending method, allows the use of all accumulating data in a sequential trial (including the estimated treatment effect) in determining the sample size for the next stage of the trial without inflating the Type I error rate. We propose a self-designing group sequential procedure to minimize the expected total cost of a trial. Cost is an important parameter to consider in the statistical design of clinical trials due to limited financial resources. Using Bayesian decision theory on the accumulating data, the design specifies sequentially the optimal sample size and proportion of the test statistic's variance needed for each stage of a trial to minimize the expected cost of the trial. The optimality is with respect to a prior distribution on the parameter of interest. Results are presented for a simple two-stage trial. This method can extend to nonmonetary costs, such as ethical costs or quality-adjusted life years.

Epidemic crack cocaine use linked with epidemics of genital ulcer disease and heterosexual HIV infection in the Bahamas: evidence of impact of prevention and control measures.

BACKGROUND: Epidemic freebase/crack cocaine use began in the Bahamas in 1982, closely followed by epidemics of genital ulcer disease (GUD) and HIV infection. Numbers of new clients receiving ambulatory treatment for cocaine use in Nassau peaked in 1984. GOAL: To assess interrelations among epidemics of crack use, GUD, and HIV infection. STUDY DESIGN: The study was designed for review and comparison of temporal trends in ambulatory and inpatient treatment of cocaine users and in numbers of cases of sexually transmitted disease (STD) and HIV infection in the Bahamas. A retrospective case-control study of cocaine use and STDs was performed at the Comprehensive Dermatovenereology Clinic in Nassau. RESULTS: Ambulatory visits and inpatient admissions for cocaine use peaked in 1984 and 1987, respectively. GUD cases increased 12-fold in the Bahamas from 1983 to the period of 1985-1987 and then declined. At the Comprehensive Dermatovenereology Clinic, gonorrhea cases outnumbered bacterial GUD cases approximately 10:1 in 1982 and 1983, but the latter increased to outnumber gonorrhea cases in 1985 and 1987-1988. Annual HIV seroprevalences at new-problem visits rose from less than 0.3% in 1986 to 12.9% by 1994 and then leveled off. Cocaine use among patients seen with STD from 1985 through 1990 was significantly associated with GUD (odds ratio [OR], 3.3; 95% CI, 2.1-5.1), secondary syphilis (OR 5.5; 95% CI, 2.4-12.6), and HIV infection (OR, 8.1; 95% CI, 4.3-15.2). CONCLUSIONS: In temporally linked successive epidemics of cocaine use, GUD, and HIV infection, case-control analyses confirmed the association of cocaine use with GUD and with HIV infection. Declining GUD and HIV seroprevalence stabilization followed declines in cocaine use and implementation of syndromic management of GUD, as well as intensified partner-notification efforts.

Surrogate end points in heart failure.

Because of the increasing number of pharmacologic strategies available for treatment of heart failure (HF), the time has come to reassess the adequacy of end points used to evaluate therapeutic efficacy. Interest in the use of surrogate end points in clinical studies is increasing. A surrogate end point is defined as a measurement that can substitute for a true end point for the purpose of comparing specific interventions or treatments in a clinical trial. A true end point is one that is of clinical importance to the patient (e.g., mortality or quality of life), whereas a surrogate end point is one biologically closer to the disease process (e.g., ejection fraction or left ventricular volume in HF). The prime motivation for the use of a surrogate end point concerns the possible reduction in sample size or trial duration. Such reductions have important cost implications and in some cases may influence trial feasibility. Another, perhaps more important, aspect of measuring surrogate end points is that they increase our understanding of the mechanism of action of drugs and thus may help physicians to take a more enlightened approach in managing their patients. In this article we have analyzed the possible potentials of the surrogate end points in clinical studies of patients with chronic HF. Other uses of possible surrogates are discussed, and the limitations in finding true surrogates are mentioned. At this time we conclude there is no well established surrogate in HF.