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Competing Interests: Declaration of Competing Interest None.

There is tremendous need for brief and supported, non-commercial youth- and caregiver-report questionnaires of youth anxiety. The pediatric and parent proxy short forms of the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety scale (8a v2.0) are free, brief, publicly accessible measures of youth- and caregiver-reported anxiety in children and adolescents. Despite increased use of the PROMIS, no study has evaluated performance of its anxiety scales in a sample of treatment-engaged anxious youth. Analyses were conducted on baseline data from the first 265 families (child M Age =11.14 years, 70% racial/ethnic minoritized youth) to enroll in the Kids FACE FEARS trial, a multisite comparative effectiveness trial of therapist-led vs. self-administered treatment for elevated youth anxiety. Confirmatory factor analysis (CFA) examined factor structure; omega coefficients and regression models examined internal consistency, convergent validity, and cross-informant reliability. CFA supported adjusted single-factor solutions across youth and caregiver reports, and internal consistency was high. Convergent validity was supported by medium-to-large associations with anxiety-related impairment and severity. Moderate cross-informant reliability between reports was found. Results showcase the first psychometric study of the PROMIS Anxiety scale short forms among treatment-engaged youth with elevated anxiety. Findings highlight the PROMIS Anxiety scale's utility in typical care settings for youth anxiety., (Published by Elsevier Ltd.)

Objective: To describe PCORnet, a clinical research network developed for patient-centered outcomes research on a national scale., Study Design and Setting: Descriptive study of the current state and future directions for PCORnet. We conducted cross-sectional analyses of the health systems and patient populations of the 9 Clinical Research Networks and 2 Health Plan Research Networks that are part of PCORnet., Results: Within the Clinical Research Networks, electronic health data are currently collected from 337 hospitals, 169,695 physicians, 3,564 primary care practices, 338 emergency departments, and 1,024 community clinics. Patients can be recruited for prospective studies from any of these clinical sites. The Clinical Research Networks have accumulated data from 80 million patients with at least one visit from 2009 to 2018. The PCORnet Health Plan Research Network population of individuals with a valid enrollment segment from 2009 to 2019 exceeds 60 million individuals, who on average have 2.63 years of follow-up., Conclusion: PCORnet's infrastructure comprises clinical data from a diverse cohort of patients and has the capacity to rapidly access these patient populations for pragmatic clinical trials, epidemiological research, and patient-centered research on rare diseases., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Opportunities to advance science increasingly arise through investigations embedded within routine clinical practice in the form of learning health systems. Such activities challenge conventional approaches to research regulation that have not caught up with those opportunities, often imposing burdens generalized from riskier research. We analyze the rules and conventions in the US, demonstrating how even those rules are compatible with a much more flexible approach to participant risk, institutional oversight, participant consent, and disclosure for low-risk learning activities in all jurisdictions., (Published by Elsevier Inc.)

Background: Universal skin and nasal decolonisation reduces multidrug-resistant pathogens and bloodstream infections in intensive care units. The effect of universal decolonisation on pathogens and infections in non-critical-care units is unknown. The aim of the ABATE Infection trial was to evaluate the use of chlorhexidine bathing in non-critical-care units, with an intervention similar to one that was found to reduce multidrug-resistant organisms and bacteraemia in intensive care units., Methods: The ABATE Infection (active bathing to eliminate infection) trial was a cluster-randomised trial of 53 hospitals comparing routine bathing to decolonisation with universal chlorhexidine and targeted nasal mupirocin in non-critical-care units. The trial was done in hospitals affiliated with HCA Healthcare and consisted of a 12-month baseline period from March 1, 2013, to Feb 28, 2014, a 2-month phase-in period from April 1, 2014, to May 31, 2014, and a 21-month intervention period from June 1, 2014, to Feb 29, 2016. Hospitals were randomised and their participating non-critical-care units assigned to either routine care or daily chlorhexidine bathing for all patients plus mupirocin for known methicillin-resistant Staphylococcus aureus (MRSA) carriers. The primary outcome was MRSA or vancomycin-resistant enterococcus clinical cultures attributed to participating units, measured in the unadjusted, intention-to-treat population as the HR for the intervention period versus the baseline period in the decolonisation group versus the HR in the routine care group. Proportional hazards models assessed differences in outcome reductions across groups, accounting for clustering within hospitals. This trial is registered with ClinicalTrials.gov, number NCT02063867., Findings: There were 189 081 patients in the baseline period and 339 902 patients (156 889 patients in the routine care group and 183 013 patients in the decolonisation group) in the intervention period across 194 non-critical-care units in 53 hospitals. For the primary outcome of unit-attributable MRSA-positive or VRE-positive clinical cultures (figure 2), the HR for the intervention period versus the baseline period was 0·79 (0·73-0·87) in the decolonisation group versus 0·87 (95% CI 0·79-0·95) in the routine care group. No difference was seen in the relative HRs (p=0·17). There were 25 (<1%) adverse events, all involving chlorhexidine, among 183 013 patients in units assigned to chlorhexidine, and none were reported for mupirocin., Interpretation: Decolonisation with universal chlorhexidine bathing and targeted mupirocin for MRSA carriers did not significantly reduce multidrug-resistant organisms in non-critical-care patients., Funding: National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Many analyses of observational data are attempts to emulate a target trial. The emulation of the target trial may fail when researchers deviate from simple principles that guide the design and analysis of randomized experiments. We review a framework to describe and prevent biases, including immortal time bias, that result from a failure to align start of follow-up, specification of eligibility, and treatment assignment. We review some analytic approaches to avoid these problems in comparative effectiveness or safety research., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Increasing morbidity related to Clostridium difficile infection (CDI) has heightened interest in the identification of patients who would most benefit from recognition of risk and intervention. We sought to develop and validate a prognostic risk score to predict CDI risk for individual patients following an outpatient healthcare visit. We assembled a cohort of Kaiser Permanente Northwest (KPNW) patients with an index outpatient visit between 2005 and 2008, and identified CDI in the year following that visit. Applying Cox regression, we synthesized a priori predictors into a CDI risk score, which we validated among a Kaiser Permanente Colorado (KPCO) cohort. We calculated and plotted the observed 1-year CDI risk for each decile of predicted risk for both cohorts. Among 356 920 KPNW patients, 608 experienced CDI, giving a 1-year incidence of 2.2 CDIs per 1000 patients. The Cox model differentiated between patients who do and do not develop CDI: there was a C-statistic of 0.83 for KPNW. The simpler points-based risk score, derived from the Cox model, was validated successfully among 296 550 KPCO patients, with no decline in the area under the receiver operating characteristic curve: 0.785 (KPNW) vs. 0.790 (KPCO). The predicted risk for CDI agreed closely with the observed risk. Our CDI risk score utilized data collected during usual care to successfully identify patients who developed CDI, discriminating them from patients at the lowest risk for CDI. Our prognostic CDI risk score provides a decision-making tool for clinicians in the outpatient setting., (Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

As HLA matching has been progressively de-emphasized in the American deceased donor (DD) kidney allocation algorithm, concerns have been raised that poor matching at first transplant may lead to greater sensitization and more difficulty finding an acceptable donor for a second transplant should the first transplant fail. We compared proportion of total observed lifetime with graft function after first transplant, and waiting times for a second transplant between individuals with different levels of HLA mismatch (MM) at first transplant. We studied patients recorded in the United States Renal Data System (1988-2009) who received a first DD transplant at age ≤21 years (n = 8433), and the subgroup who were listed for a second DD transplant following first graft failure (n = 2498). Compared with recipients of 2-3 MM first grafts, 4-6 MM graft recipients spent 12% less of their time and 0-1 MM recipients 15% more time with a functioning graft after the first transplant (both p < 0.0001); 4-6 MM recipients were significantly less likely (hazard ratio [HR] 0.87 [95% confidence interval 0.76, 0.98]; p = 0.03), and 0-1 MM recipients more likely (HR 1.26 [0.99, 1.60]; p = 0.06) to receive a second transplant after listing. The benefits of better HLA matching at first transplant on lifetime with graft function are significant, but relatively small., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Mortality risk for kidney transplant recipients may change with increasing accumulated exposure to the "transplantation milieu." We sought to characterize changes over time in mortality rate and in age-, sex- and race-standardized mortality ratios (SMR) relative to the general population, and to estimate the association between increasing time since first transplant and mortality risk. A total of 18 911 patients who received a first transplant at <21 years old (1983-2006), and whose data were recorded in the USRDS, were studied. There were 2713 deaths over a median follow-up of 8.9 (interquartile range 4.0-14.5; maximum 23) years. Among those with graft function, mortality was highest in the first post transplant year; beyond the first year of the first transplant, age-adjusted mortality rates and SMRs decreased slightly over follow-up. Cause of death was cardiovascular for 34.6%, infection for 19.5%, malignancy for 5.8%, other for 21.4% and unknown for 18.7%. For every 1-year time increment after the end of the first post transplant year, age-adjusted all-cause and cardiovascular mortality rates fell by 1% (p = 0.06) and 16% (p = 0.007), respectively; infection-related mortality rate did not change over time (p = 0.5). These results suggest that exposure to the transplantation milieu has no cumulative negative effects on cardiovascular health over the long term., (©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: To assess the predictive value of claims-based outpatient urticaria diagnosis codes to identify potential vaccine-related adverse events (AEs) when recorded on the same day as influenza vaccination., Study Design and Setting: Health plan members with outpatient claims for influenza vaccination and urticaria on the same day between October 1, 2002, and December 31, 2007, were eligible for inclusion. Electronic medical records (EMRs) for 50 eligible patients with the most recent visits of interest occurring at a large group practice were sampled for review., Results: EMRs were available and reviewed for 42 of 50 patients. An influenza vaccination was confirmed in all reviewed medical charts. Urticaria occurring on the day of influenza vaccination was confirmed for 40% of participants (17/42); 3 confirmed urticaria diagnoses were potential AEs and 14 urticaria events occurred before vaccination. Among those with unconfirmed diagnoses, 17 had no evidence of urticaria on physical examination on the day of interest (4 had evidence of a nonurticarial rash and 13 had no evidence of rash on examination) and 8 had insufficient information to make a clinical determination., Conclusion: Outpatient diagnosis codes for urticaria found in health insurance claims data are limited in their predictive value to identify same-day vaccine AEs., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: We sought to evaluate the association between inherited thrombophilia and preeclampsia., Study Design: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia and selected 443 control subjects who did not have preeclampsia or nonproteinuric gestational hypertension. Blood samples were tested for DNA polymorphisms affecting thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T polymorphism), homocysteine, and folate levels, and placentae underwent pathological evaluation., Results: Thrombophilia was present in 14% of patients and 21% of control subjects (adjusted logistic regression odds ratio, 0.6; 95% confidence interval, 0.3-1.3). Placental underperfusion was present in 63% of patients vs 46% of control subjects (P < .001) and was more frequent in women with folate levels in the lowest quartile (P = .04), but was not associated with thrombophilia., Conclusion: We did not find evidence to support an association between inherited thrombophilia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophilia.

Objective: To assess the usefulness of health plan administrative data for identifying patients with irritable bowel syndrome (IBS)., Study Design and Setting: In this retrospective study of 442 medical records of patients in nine U.S. health plans, five sets of criteria that used administrative data were used to identify potential IBS patients. Physician reviewers provided an assessment of the likelihood of the diagnosis of IBS being present. IBS was considered to be present if the physician reviewer categorized the case as definite, probable, or possible based on medical record review. Analyses were also performed with cases categorized as possible placed in an "IBS not present" category., Results: The positive predictive value (PPV) for the five sets of criteria ranged from 63% to 83% with the highest PPV found with one of the most restrictive criteria. When cases characterized as possible were included in the "IBS not present" category, the PPV for each of the five sets of criteria decreased substantially, ranging from 33% to 63%., Conclusion: The PPV of different criteria used to identify patients with IBS from administrative data varies substantially based on the criteria that are used. Use of criteria with a higher PPV may come at the expense of generalizability.

Objective: This study was undertaken to provide information on the prevalence of use of antidepressant drugs among pregnant women in the United States., Study Design: A retrospective study was conducted using the automated databases of 7 health plans. Women who delivered an infant in a hospital were identified. Antidepressant drug use was evaluated assuming a gestational duration of 270 days., Results: Among the 118,935 deliveries occurring from 2001-2005, 6.6% of women were dispensed an antidepressant during pregnancy. Antidepressant drug use increased from 2.0% in 1996 to 7.6% of deliveries in 2004 and 2005. Selective serotonin reuptake inhibitor use increased from 1.5% in 1996 to 6.4% in 2004 and 6.2% in 2005., Conclusion: Our finding that nearly 8% of pregnant women were prescribed antidepressants drugs during the years 2004 and 2005 highlights the importance of understanding the effects of these medications on the developing fetus and on the pregnant woman.

Purpose: Persistence with ocular hypotensive medication is important as a long-term outcome, and rates of persistence typically are low. This study assessed restart rates for 3 prostaglandin analogs by determining the percentage of patients who discontinued and then restarted therapy., Design: Retrospective cohort study of pharmacy claims submitted to a large national administrative claims database., Participants: In all, 4356 patients initiating prostaglandin therapy were identified., Methods: Claims for 3 prostaglandin analogs (bimatoprost, latanoprost, travoprost [index prostaglandin]) submitted between 2001 and 2002 were analyzed. Patients were excluded if they did not have coverage in the plan for the preceding 180 days or had been prescribed any ocular prostaglandin in the prior 180 days., Main Outcome Measures: Persistence was defined as neither discontinuing nor changing the index prostaglandin. The number of current users of the index prostaglandin at day 180 was the sum of patients who persisted with the index prostaglandin plus patients who restarted the index prostaglandin after a discontinuation., Results: Of the 4356 patients initiating prostaglandin therapy, 2503 (57%) were potential current users (were still plan members and had not switched ocular hypotensive therapies after 180 days). Just over half, (1356/2503 [54%]) were current users, including 879 (35%) who persisted with their index prostaglandin and 477 (19%) who restarted their index prostaglandin. Of patients discontinuing their index prostaglandin, more than half failed to restart any topical therapy (827/1624 [51%])., Conclusions: Previous studies showing low persistence rates for glaucoma therapy failed to evaluate restarts. Restart analyses are crucial for assessing long-term treatment of chronic diseases such as glaucoma. In general, persistence remains a challenge, and our findings demonstrate the importance of clinicians' identifying patients who are not persistent and encouraging them either to restart or to initiate treatment with an alternative therapy.

Introduction: Secondary prevention is needed following coronary artery bypass graft (CABG) surgery to reduce the subsequent risk of unstable angina, myocardial infarction and death. However, little research exists on the use of cardiovascular medical therapy in CABG surgery patients. The objective of the present study is to describe the use of cardiovascular medical therapy among patients discharged after CABG surgery., Methods: The use of acetylsalicylic acid, clopidogrel, warfarin, antilipid agents, beta-blockers, calcium channel blockers, nitrates and angiotensin-converting enzyme (ACE) inhibitors was examined among 320 patients enrolled in the Routine versus Selective Exercise Treadmill Testing After Coronary Artery Bypass Graft Surgery (ROSETTA-CABG) Registry. Logistic regression identified the determinants of medication use at 12 months following CABG surgery., Results: Most patients were male, hyperlipidemic and underwent CABG surgery for relief of angina symptoms. At admission, discharge and at 12 months, acetylsalicylic acid was used in 71%, 92% and 87% of cases, respectively, and some form of antiplatelet agent was used in 74%, 94% and 89% of cases, respectively. The use of antilipid agents remained constant, from 55% at admission to 57% at discharge. However, 24% of patients were not receiving antilipid agents at 12 months. The use of beta-blockers was 57% at admission, 71% at discharge and 64% at 12 months. The use of calcium channel blockers and nitrates decreased modestly from admission to discharge and remained stable at approximately 20% and 22%, respectively, at 12 months. ACE inhibitor use remained stable, from 33% at admission to 38% at 12-months. Hyperlipidemia, hypertension, obesity and pre-CABG surgery left ventricular ejection fraction less than 40% were all found to be important determinants of 12-month medication use. Importantly, the use at discharge was an important determinant of 12-month use of for each medication examined in the present study., Conclusions: The use of antilipid agents, beta-blockers and ACE inhibitors was found to be too low among post-CABG surgery patients, who are known to benefit from their use, and the use of nitrates was too high. Discharge from hospital provides a unique opportunity for physicians to modify the use of cardiovascular medical therapy among patients undergoing CABG surgery.

Background: Objective measurements are notably lacking for many adverse events in health care. A new approach to monitoring such events is based on the experience in measuring hospital-associated infections., Developing Objective and Universal Measures: An essential tenet of the current goal of surveillance-focusing only on rigorously confirmed adverse events-is neither necessary nor achievable across the entire health care system. Efforts should be directed instead to creating objective measures of quality of care and of outcomes that can be used by all health care facilities. Adopting objective measures would be easier if health care was open to surrogate measures of important outcomes. Surrogate measures of interest for infection surveillance are used to identify objective, readily ascertained events that are sufficiently correlated with infections to provide useful information about organizations' infection rates. For example, the surgical site infection rate following coronary artery bypass appears to correlate closely enough with the proportion of patients who receive extended courses of inpatient antibiotics to be a useful indicator of a hospital's outcomes for the procedure., Conclusion: Developing clinically relevant process or surrogate measures that clinicians would use to improve patient outcomes is essential. These measures could be relevant not only to hospital-acquired infections but other health care-related adverse events that are relatively common yet require substantial resources to identify.

Objective: We evaluated the positive predictive values (PPVs) of specific criteria based upon International Classification of Diseases, 9th revision (ICD-9-CM) codes documented in health plan administrative databases for identification of cases of serious myopathy and rhabdomyolysis., Study Design and Setting: We conducted a retrospective study among patients enrolled in 11 geographically dispersed managed care organizations. Cohorts of new users of specific statins and fibrates were identified by selecting patients with an initial dispensing of the drug during the period 1 January 1998 to 30 June 2001. Potential cases of serious myopathy or rhabdomyolysis were identified using specific criteria based upon ICD-9-CM codes suggesting a muscle disorder or acute renal failure., Results: A total of 194 hospitalizations meeting the criteria for chart review selection were identified among 206,732 new users of statins and 15,485 new users of fibrates. Overall, 31 cases of serious, clinically important myopathy or rhabdomyolysis (18%) were confirmed through chart review. Of these, 26 (84%) had a claim including codes for myoglobinuria (ICD-9-CM 791.3) or other disorders of muscle, ligament, and fascia (ICD-9-CM 728.89). A PPV of 74% (26 of 35 patients meeting criteria) was found for a composite definition that included (1) a primary or secondary discharge code for myoglobinuria, (2) a primary code for "other disorders of muscle," or (3) a secondary code for "other disorders of muscle" accompanied by a claim for a CK test within 7 days of hospitalization or a discharge code for acute renal failure., Conclusion: For rare adverse events such as serious myopathy or rhabdomyolysis, large population-based databases that include diagnosis and laboratory test claims data can facilitate epidemiologic research.

Objective: The purpose of this study was to provide information on the prevalence of the use of prescription drugs among pregnant women in the United States., Study Design: A retrospective study was conducted with the use of the automated databases of 8 health maintenance organizations that are involved in the Health Maintenance Research Network Center for Education and Research on Therapeutics. Women who delivered of an infant in a hospital from January 1, 1996, through December 31, 2000, were identified. Prescription drug use according to therapeutic class and the United States Food and Drug Administration risk classification system was evaluated, with the assumption of a gestational duration of 270 days, with three 90-day trimesters of pregnancy, and with a 90-day period before pregnancy. Nonprescription drug use was not assessed., Results: During the period 1996 through 2000, 152,531 deliveries were identified that met the criteria for study. For 98,182 deliveries (64%), a drug other than a vitamin or mineral supplement was prescribed in the 270 days before delivery: 3595 women (2.4%) received a drug from category A; 76,292 women (50.0%) received a drug from category B; 57,604 women (37.8%) received a drug from category C; 7333 women (4.8%) received a drug from category D, and 6976 women (4.6%) received a drug from category X of the United States Food and Drug Administration risk classification system. Overall, 5157 women (3.4%) received a category D drug, and 1653 women (1.1%) received a category X drug after the initial prenatal care visit., Conclusion: Our finding that almost one half of all pregnant women received prescription drugs from categories C, D, or X of the United States Food and Drug Administration risk classification system highlights the importance of the need to understand the effects of these medications on the developing fetus and on the pregnant woman.

It is widely accepted that meta-analysts should search multiple databases. The selection of databases is ideally based on the potential contribution of each database to the project or on the potential for bias if a database is excluded, as supported by research evidence. We explore whether searching Embase yields additional trials that influence a meta-analysis. We identified meta-analyses that searched Medline and Embase. A random-effects weighted mean method was used to estimate the intervention effect in articles indexed only in Embase compared with those indexed elsewhere. On average, Embase-unique trials yielded significantly smaller estimates by 29% (ratio of odds ratio [ROR] 0.71, 95% confidence interval [CI] 0.56-0.90) but influenced the pooled estimate by an average of only 6% (ROR 0.94, 95% CI 0.88-0.99). Searching Medline but not Embase risks biasing a meta-analysis by finding studies that show larger estimates, but their prevalence seems low enough that the risk may be slight, provided the rest of the search is comprehensive.

Objectives: To 1) describe barriers to pneumococcal conjugate vaccine adoption and 2) estimate the value of the vaccine based on pediatricians' responses to willingness-to-pay questions., Methods: In June 2000, we mailed a random sample of pediatricians in Massachusetts a questionnaire about barriers to adoption of the vaccine and willingness to pay for the vaccine and associated outcomes. Respondents were assigned at random to 1 of 2 survey versions: the Personal Perspective version, for which they imagined spending their own money for their own child, or the Public Perspective version, for which they imagined spending the government's money for the average child., Results: Of the 546 pediatricians who responded (estimated completion rate, 80%), only 9% were using the vaccine routinely at the time of the survey. Most said that if the state did not provide the vaccine, financial barriers including inadequate insurance reimbursement would limit their use of the vaccine either a great deal (61%) or a moderate amount (25%). Pediatricians who were asked how much they would pay for the vaccine for their own child (personal perspective) gave a mean of $56 per dose, whereas those who were asked how much the government should pay on behalf of an average child (public perspective) gave a mean of $36 per dose. Alternatively, when we used a decision analysis model and incorporated pediatricians' values for preventing pneumococcal infections to estimate the vaccine's value, the value per dose was $38 from the personal perspective and $34 from the public perspective., Conclusions: Pediatricians in Massachusetts identified significant financial barriers to the adoption of pneumococcal conjugate vaccine related to insurance arrangements. Based on willingness-to-pay questions, the value of the vaccine is lower than the current list price. The methods used to estimate the value of a vaccine, including the perspective used to frame questions, may substantially influence the results.

The automated health plan data and data from medical chart abstractions from eight large health maintenance organizations were used to evaluate the positive predictive values (PPVs) of the International Classification of Diseases, 9th revision (ICD-9) codes for cases of peptic ulcers and upper gastrointestinal bleeding. Overall, 207 of 884 cases of peptic ulcers and upper gastrointestinal bleeding (23%) were confirmed by surgery, endoscopy, X-ray, or autopsy. The PPVs were 66% for hospitalizations with codes for duodenal ulcer (ICD-9-CM 532), 61% for gastric/gastrojejunal ulcer (ICD-9-CM 531, 534), 1% for peptic ulcer (ICD-9-CM 533), and 9% for gastrointestinal hemorrhage (ICD-9-CM578). The overall and diagnostic category-specific PPVs were generally similar for the various HMOs. This study, using data from a large number of health plans located in different geographical regions, underscores the importance of evaluating the accuracy of the diagnoses from automated health plan databases.

Trials provide most of the data on the incidence of hypoglycemia in patients with diabetes. However, trial protocols may not reflect changes in diabetes management that occur over time. Using a retrospective cohort design, we calculated the incidence of hypoglycemia in 1,113 patients 20 to 64 years of age who used insulin monotherapy from 1993 through 1997 at Harvard Pilgrim Health Care, a health maintenance organization (HMO) in New England. Episodes included emergency department visits or hospital admissions for hypoglycemia identified through insurance claims and documented in patients' medical records. The incidence of hypoglycemia was 5.07 episodes per 100 person-years (95% CI, 4.14 to 6.00); 203 confirmed episodes occurred in 129 unique patients during 4,005 person-years of follow-up. The incidence increased by approximately 24% per year (rate ratio = 1.24; 95% CI, 1.11 to 1.38) from 1993 through 1997, perhaps reflecting physicians' and patients' efforts to intensify glucose management.

Background: While parenteral amphotericin B is an effective therapy for serious fungal infections, it frequently causes acute renal failure (ARF). This study identified correlates of ARF in amphotericin B therapy and used them to develop clinical prediction rules., Methods: All 643 inpatients receiving parenteral amphotericin B therapy at one tertiary care hospital were included. Data regarding correlates were obtained both electronically and from manual chart review in a subsample of 231 patients. ARF was defined as a 50% increase in the baseline creatinine with a peak > or =2.0 mg/dL., Results: Among 643 episodes, ARF developed in 175 (27%). In the larger group, the only independent correlate of ARF was male gender (OR = 2.2, 95% CI, 1.5 to 3.3). In the subsample (N = 231), independent correlates of ARF were maximum daily amphotericin dosage, location at the time of initiation of amphotericin therapy, and concomitant use of cyclosporine. These data were used to develop two clinical prediction rules. A rule using only data available at initiation of therapy stratified patients into groups with probability of ARF ranging from 15 to 54%, while a rule including data available during therapy (maximum daily dose) stratified patients into groups with probability of ARF ranging from 4 to 80%., Conclusions: Acute renal failure occurred in a quarter of the patients. Correlates of ARF at the beginning and during the course of amphotericin therapy were identified and then combined to allow stratification according to ARF risk. These data also provide evidence for guidelines for the selection of patients for alternative therapies.

Numerous adherence variables have been created from electronic dosing records hindering synthesis of the vast body of adherence research. To elucidate the mathematical foundation for electronic adherence monitoring and to understand how diverse electronic adherence metrics are related to each other and the underlying construct of adherence behavior. Several representative adherence metrics are derived mathematically and their relationship to the underlying consumption (or dosing event) rate analyzed. Data from a 3-month study of 286 individuals on single-drug antihypertensive therapy are then used to empirically study the statistical properties of several of these electronic adherence metrics. As suggested by their common link to the consumption (or dosing event) rate, the analyzed electronic adherence metrics were generally strongly correlated (r <- .6 and > .4). The lowest correlation (r = .15) involved the ratio of the observed number of doses to the recommended number (called average adherence), which tended to emphasize quantity consumed, and the ratio of the observed to maximum mean squared rate deviation (MSRD ratio), which focused more on dose timing. Despite their different formulations, electronic adherence variables are generally closely correlated. Adherence metrics that average the consumption rate over multiple doses (by summing up the number of doses and dividing by the monitored time) may be less sensitive to short-term fluctuations in medication intake. Metrics that are more sensitive to timing variability may thus be preferable when timing as well as quantity of dosing are of interest.

Objective: The purpose of this study was to analyze cervical dilatation patterns among women with uterine rupture by means of a mathematic model and to use the results to determine optimal intervention criteria., Study Design: This was a case-control review that compared a case patient group of 19 women with uterine rupture during labor with control groups with either no previous cesarean deliveries, vaginal birth after cesarean delivery, or failure of attempted vaginal birth after cesarean delivery. The mathematic model quantified dilatation and adjusted for conditions specific to each patient. Case patients were compared with matched control subjects by means of paired t tests, analysis of variance, odds ratios, and conditional logistic regression., Results: Dystocia was present in 31.6% to 47.4% of patients with uterine rupture, versus 2.6% to 13.2% of the control group with no previous cesarean deliveries (P< or =.001). The incidence of an arrest disorder among patients with uterine rupture was similar to that seen in the control group with failure of attempted vaginal birth after cesarean delivery. However, the interval from diagnosis to rupture or cesarean delivery was 5.5 +/- 3.3 hours among case patients with uterine rupture and 1.5 +/- 1.3 hours in the control group with failure of attempted vaginal birth after cesarean delivery., Conclusion: When cervical dilatation was lower than the 10th percentile and was arrested for > or =2 hours, cesarean delivery would have prevented 42.1% of the cases of uterine rupture and resulted in excess 2.6% and 7.9% cesarean delivery rates among women with no previous cesarean deliveries and women with vaginal birth after cesarean delivery, respectively.

Background: Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women., Methods: We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis., Findings: There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs., Interpretation: Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Objective: To determine factors explaining lack of response by preterm newborns to heel stick for blood sampling., Design: A cross-sectional design based on secondary analysis of the control session of a randomized crossover design., Setting: Four Level III neonatal intensive-care units of university teaching hospitals., Participants: 120 preterm newborns with an average age of 28 weeks postconceptional age., Intervention: 24 newborns who showed a "no change" response according the Premature Infant Pain Profile were compared to the remaining 96 newborns who had shown a pain response., Main Outcome Measures: Age (postconceptional age at birth, postnatal age at study), Apgar score at 5 minutes, severity of illness, sex, race, wake/sleep state, previous study sessions, total number of painful procedures since birth, and time since last painful procedure., Results: After stepwise logistic regression analysis the variables remaining in the final model that explained the difference between the groups were postnatal age at time of study, postconceptional age at birth, time since last painful procedure, and wake/sleep state., Conclusions: Newborns who were younger, asleep, and had undergone a painful event more recently were less likely to demonstrate behavioral and physiologic indicators of pain.

Objective: Our purpose was to evaluate a possible relationship between adhesion-related small-bowel obstruction and gynecologic operations., Study Design: The records of all female patients with the diagnosis of small-bowel obstruction from 1989 to 1996 were studied. The cause of bowel obstruction, the type and technique of previous operations, and whether the parietal peritoneum was closed at the completion of the procedure or was left open were evaluated., Results: Among 262 women the most common cause of small-bowel obstruction was intra-abdominal adhesions (37.0%). Among 92 women with adhesion-related small-bowel obstruction, 35 women (38%) had undergone a previous abdominal hysterectomy. The incidence of small-bowel obstruction after an abdominal hysterectomy was 16.3 per 1000 hysterectomies. The incidence of small-bowel obstruction after cesarean delivery (5/10,000 cesarean deliveries) was significantly less than after other abdominal operations. Adhesions were found between the small bowel and the pelvis in 14 women (29.8%), and all were in women who had undergone a hysterectomy. In 33 others (70.2%) the adhesions were found between the previous abdominal incision and the intestine. The median interval between the initial operation and the small-bowel obstruction was 5.3 years., Conclusion: The most common cause of small-bowel obstruction is postsurgical adhesions. Adhesionrelated small-bowel obstruction is commonly found after an abdominal hysterectomy. Bowel obstruction can occur many years after the initial abdominal surgery.

Objective: The objective was to determine whether small twins had a survival advantage with respect to small singletons after controlling for other factors associated with adverse perinatal outcome., Study Design: A hospital-based cohort study included all births between 1980 and 1995 of babies born between 24 and 43 weeks' gestation. Logistic regression was used to estimate the perinatal mortality risks for monochorionic and dichorionic twins with growth restriction after adjusting for gestational age, maternal age, parity, method of delivery, and the presence or absence of congenital malformations., Results: The study sample included 1062 dichorionic twins, 354 monochorionic twins, and 59,873 singletons. Small monochorionic and dichorionic twins showed a similar overall risk of perinatal mortality (odds ratio 1.40, confidence interval 0.86 to 2.25). However, monochorionic twins with birth weights <10th percentile faced an increased risk of perinatal death compared with singletons (odds ratio 2.45, confidence interval 1.20 to 5.02). Dichorionic twins had no such increased risk (odds ratio 0.91, confidence interval 0.45 to 1.84)., Conclusions: Twins with growth restriction are not protected against perinatal loss, even after adjusting for congenital malformations. In fact, monochorionic twins are more than twice as likely to die in the perinatal period as are their singleton counterparts.

Purpose: To investigate the possible association between ibuprofen use and dermatologic superinfections among children with recent varicella infection., Methods: A retrospective cohort study of children in Harvard Pilgrim Health Care, a health maintenance organization in New England, was conducted. Outcomes and exposures of interest were identified from automated medical and pharmacy records. Exposure was defined by dispensing of ibuprofen before varicella to avoid potential confounding by indication., Results: Between July 1, 1990 and September 30, 1994, 89 superinfections developed among 7,013 cases of varicella. The 30-day risk of superinfection was 7.2/10(3) cases (95% CI = 5.8-8.8/10(3) cases). Four of 169 children dispensed ibuprofen within 180 days of varicella developed superinfection. Relative to children without prior use, children with ibuprofen dispensed in the month prior to varicella were 3.1 times more likely to be diagnosed with a superinfection (95% CI = 0.1-19.7; P-value: 0.31). Restriction of outcomes to superinfections treated with systemic antibiotics increased the odds ratio to 5.1 (95% CI = 0.1-32.5; P-value: 0.22)., Conclusions: The results of this study are consistent with a broad range of effects including no association and suggest that further study is needed.

We studied the occurrence of depression in new users of propranolol (n = 704), other beta-blockers (n = 587), angiotensin-converting enzyme inhibitors (n = 976), calcium channel blockers (n = 742), and diuretics (n = 773) in the Harvard Community Health Plan population. The period of the study was from April 1988 to June 1991. All study subjects were followed for new or newly recurrent depression for up to 6 months after receiving their first study prescription. Case status was confirmed by blinded medical record review. We found 10 cases of depression that met DSM-III-R criteria ("major depression") and an additional 18 cases that had one or more symptoms consistent with depression ("minor depression"). Rates of major depression in users of beta-blockers and users of non-beta-blocker study drugs were 5.8 per 1000 person-years of exposure and 9.6 per 1000 person-years, respectively. None of the cases of major depression was propranolol associated. Rates of major or minor depression (combined) in users of beta-blockers and users of non-beta-blockers were 20.2 per 1000 person-years and 25.2 per 1000 person-years, respectively. The age- and sex-adjusted relative risk of major or minor depression associated with the use of beta-blockers compared to non-beta-blockers was 0.8 (95% CI, 0.3-1.9). The relative risk associated with propranolol compared to non-beta-blockers was also 0.8 (95% CI, 0.1-2.7). Therefore, depression occurred no more frequently in beta-blocker users than in other members of the study base.

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

Reversible hematologic abnormalities including hemolytic anemia [1] with a positive direct Coombs' test have been associated with ranitidine. In addition to the case report cited above, the U.S. Food and Drug Administration had received five other cases of hemolysis associated with recent intake of ranitidine as of February 1991. To investigate the possible association of ranitidine with autoimmune hemolytic anemia, a study was conducted to determine how often diagnoses of hemolytic anemia or abnormal Coombs' test results followed dispensing of ranitidine using the automated medical and pharmacy records of a large health maintenance organization. No occurrences of hemolytic anemia were identified among 12,054 individuals following 38,686 prescriptions for this medication. The 95% upper confidence bound was 3.1 cases/10,000 exposed persons. One abnormal direct Coombs' test with mild anemia was discovered during routine prenatal testing of an asymptomatic patient who was dispensed ranitidine two and a half months previously. Hemolysis, however, was not demonstrated and an association with prior ranitidine use could not be confirmed. Additional analyses indicate that in only 30% of ranitidine courses was a blood count obtained. In those courses with hematocrits below 40%, less than 1% had a Coombs' test performed. Chart review suggests that the majority of individuals with severe anemia have alternative explanations other than autoimmune hemolysis for their anemia. This analysis indicates that ranitidine is unlikely to be a common cause of clinically recognized autoimmune hemolytic anemia and demonstrates the utility of large automated medical and pharmacy data bases to conduct post-marketing studies of spontaneously reported drug effects.

In four experiments with 760 subjects, the present study examined Cosmides' Darwinian algorithm theory of reasoning: specifically, its explanation of facilitation on the Wason selection task. The first experiment replicated Cosmides' finding of facilitation for social contract versions of the selection task, using both her multiple-problem format and a single-problem format. Experiment 2 examined performance on Cosmides' three main social contract problems while manipulating the perspective of the subject and the presence and absence of cost-benefit information. The presence of cost-benefit information improved performance in two of the three problems while the perspective manipulation had no effect. In Experiment 3, the cost-benefit effect was replicated; and performance on one of the three problems was enhanced by the presence of explicit negatives on the NOT-P and NOT-Q cards. Experiment 4 examined the role of the deontic term "must" in the facilitation observed for two of the social contract problems. The presence of "must" led to a significant improvement in performance. The results of these experiments are strongly supportive of social contract theory in that cost-benefit information is necessary for substantial facilitation to be observed in Cosmides' problems. These findings also suggest the presence of other cues that can help guide subjects to a deontic social contract interpretation when the social contract nature of the problem is not clear.

The authors used a two-stage design to compare the risk of endometritis in women undergoing non-elective cesarean section who received cefazolin prophylaxis (n = 481) with those who received cefoxitin prophylaxis (n = 1799). The primary data source for this study was an automated record linkage system which allowed the ascertainment of exposure(antibiotic prophylaxis) and preliminary ascertainment of outcome (post-partum endometritis) on a consecutive sample of women undergoing cesarean section between 1 April 1987 and 30 September 1989. Potentially important covariates not available in the automated data source were sampled by review of complete medical records of a random sample of each exposure-disease category of the cohort. Of the 2280 women studied, 99 (4.3%) developed postpartum endometritis. After control for age, race, anemia, presence of ruptured membranes, parity, labor, number of vaginal examinations and payor status the adjusted odds ratio for cefazolin compared to cefoxitin was 0.95 (95% C.I. 0.5-1.9). The cost of prophylaxis was significantly higher for women who received cefoxitin prophylaxis ($56/patient vs $9.55/patient). These results suggest that cefazolin prophylaxis should be favored over cefoxitin due to lower cost and similar efficacy. This study also demonstrates the efficiency of a two-stage design in the setting where exposure and outcome are available for an entire cohort but information about important covariates is more difficult to obtain.

A randomised controlled trial was conducted to assess whether bladder catheters with preconnected sealed junctions were associated with a lower risk of urinary-tract infection than were catheters without such junctions, and to determine whether prevention of catheter-associated infection would be accompanied by a reduction of mortality. Among those not taking systemic antibiotics, patients assigned sealed junction catheters had fewer infections and deaths. Before they received antibiotics, the risk of infection among those assigned unsealed catheters was 2.7 times that of patients assigned sealed catheters (95% confidence interval=1.3-5 . 4, p=0 . 007). Among the 220 patients who received no antibiotics, 14% (15/108) of those assigned unsealed catheters and 4% (4/112) of those assigned sealed catheters died. Stratification by important risk factors for mortality yielded an adjusted risk ratio for death of 3.4 (95% CI=1.1-10.7, p=0.03). Among patients who received systemic antibiotic the use of sealed catheters did not affect infection rates (RR=0.9, 95% CI=0.5-1.5, p=0.68) or deaths (RR=1.2, 95% CI=0.6-2.2, p=0.62). These data indicate how the rates of infection and mortality can be reduced in hospital. Since the degree of reduction in mortality corresponded with the degree of reduction of infection, measures to prevent catheter-associated nosocomial urinary tract infection should be implemented.

A follow-up of 535 patients after vaginal delivery showed that 9% had a fever of 37.7 degrees C or greater, and 2% had a fever of 38 degrees C or more, on two days. The commonest cause of both categories of fever was Mycoplasma hominis infection as defined by a fourfold or greater rise in mycoplasmacidal antibody titre. Among women for whom sera were available this agent caused 50% (14/28) of all fevers and 71% (5/7) of the higher fevers. Absence or low titre (< 1:8) of antibody against M. hominis was the strongest single predictor of otherwise unexplained fever (16/40 patients with low antibody titre were febrile vs 7/50 with high antibody titre, p < 0.01). Among women with absent or low antibody titres, both rise in titre of antibody to this organism and lochial colonisation by it were significantly associated with fever (p < 0.001, p < 0.025, respectively). Standard microbiological and clinical techniques identified probable causes in only 18% (5/28) of all fevers and 29% (2/7) of higher fevers. Patients who had postpartum infection caused by M. hominis remained in hospital 31% longer than the non-infected patients (4.57 vs 3.49 days, p < 0.001). Low antibody to and lochial colonisation with M. hominis occurred together in 17% of patients, who accounted for 71% of all higher fevers. Since these risk factors for postpartum fever can be identified before delivery, prophylactic measures applied selectively to women with these risk factors may prevent a large proportion of postpartum fevers and the excess hospital stay associated with them.