Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction.

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite the development of many methods for amine preparation, C(sp3)-rich nitrogen-containing compounds continue to pose challenges for synthesis. While carbonyl reductive amination (CRA) between ketones and alkylamines is the cornerstone method for α-branched alkylamine synthesis, it is sometimes limited by the sterically demanding condensation step between dialkyl ketones and amines and the more restricted availability of ketones compared to aldehydes. We recently reported a "higher-order" variant of this transformation, carbonyl alkylative amination (CAA), which utilized a halogen atom transfer (XAT)-mediated radical mechanism, enabling the streamlined synthesis of complex α-branched alkylamines. Despite the efficacy of this visible-light-driven approach, it displayed scalability issues, and competitive reductive amination was a problem for certain substrate classes, limiting applicability. Here, we report a change in the reaction regime that expands the CAA platform through the realization of an extremely broad zinc-mediated CAA reaction. This new strategy enabled elimination of competitive CRA, simplified purification, and improved reaction scope. Furthermore, this new reaction harnessed carboxylic acid derivatives as alkyl donors and facilitated the synthesis of α-trialkyl tertiary amines, which cannot be accessed via CRA. This Zn-mediated CAA reaction can be carried out at a variety of scales, from a 10 µmol setup in microtiter plates enabling high-throughput experimentation, to the gram-scale synthesis of medicinally-relevant compounds. We believe that this transformation enables robust, efficient, and economical access to α-branched alkylamines and provides a viable alternative to the current benchmark methods.

Trends in elective labor induction for six United States health plans, 2001-2007.

BACKGROUND: To describe trends in labor induction, including elective induction, from 2001 to 2007 for six U.S. health plans and to examine the validity of induction measures derived from birth certificate and health plan data. METHODS: This retrospective cohort study included 339,123 deliveries at 35 weeks' gestation or greater. Linked health plan and birth certificate data provided information about induction, maternal medical conditions, and pregnancy complications. Induction was defined from diagnosis and procedure codes and birth certificate data and considered elective if no accepted indication was coded. We calculated induction prevalence across health plans and years. At four health plans, we reviewed medical records to validate induction measures. RESULTS: Based on electronic data, induction prevalence rose from 28% in 2001 to 32% in 2005, then declined to 29% in 2007. The trend was driven by changes in the prevalence of apparent elective induction, which rose from 11% in 2001 to 14% in 2005 and then declined to 11% in 2007. The trend was similar for subgroups by parity and gestational age. Elective induction prevalence varied considerably across plans. On review of 86 records, 36% of apparent elective inductions identified from electronic data were confirmed as valid. CONCLUSIONS: Elective induction appeared to peak in 2005 and then decline. The decrease may reflect quality improvement initiatives or changes in policies, patient or provider attitudes, or coding practices. The low validation rate for measures of elective induction defined from electronic data has important implications for existing quality measures and for research studies examining induction's outcomes.

Methods of linking mothers and infants using health plan data for studies of pregnancy outcomes.

PURPOSE: Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research. METHODS: We describe how eight sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001-2007 birth cohorts. We describe linkage rates across sites, and for two sites, we compare the characteristics of populations linked using different methods. RESULTS: Of 299,260 deliveries, 256,563 (86%; range by site, 74-99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother-infant linkage increased the representation of mothers who were Hispanic or non-White, younger, Medicaid recipients, or had low educational level. A total of 236,460 (92%; range by site, 82-100%) deliveries could be linked to a birth certificate. CONCLUSIONS: Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry.

Are benefits from diabetes self-management education sustained?

OBJECTIVES: To evaluate whether outcomes from diabetes self-management education for patients with suboptimal control were sustained. STUDY DESIGN: A randomized controlled trial of 623 adults with type 2 diabetes and glycated hemoglobin (A1C) > 7% assigned to receive conventional individual education (IE), group education (GE) using US Diabetes Conversation Maps, or usual care (UC) with no education. METHODS: A1C tests, Problem Areas in Diabetes (PAID), Diabetes Self-Efficacy (DES), Recommended Food Score (RFS), physical activity, and medication use were quantified at baseline and 1 year of follow-up through electronic health records and quarterly mailed surveys. Short-term (mean 6.8 months) and long-term (12.8 months) outcomes were evaluated using linear mixed models. In addition, follow-up trajectories were plotted in a random effects generalized additive model with smooth splines. RESULTS: Compared with UC, IE resulted in long-term improved DES and PAID scores (DES, +.11, P = .03 and PAID, -2.94, P = .04), but not significantly improved long-term RFS or physical activity change. The A1C trajectory declined more steeply in IE than GE and UC for the first 150 days post randomization. However, by 250 days, there was no treatment group A1C difference. The model fit likelihood ratio test for A1C intervention trends was significant for 3 distinct non-linear trajectories (P = .02). CONCLUSIONS: Conventional IE (but not GE) resulted in significant and sustained improvements in self-efficacy and reduced diabetes distress compared with UC, but short-term improvements in A1C, nutrition, and physical activity were not sustained. Patients may need ongoing reinforcement to achieve lasting behavioral change and glucose control.

Validity of health plan and birth certificate data for pregnancy research.

PURPOSE: To evaluate the validity of health plan and birth certificate data for pregnancy research. METHODS: A retrospective study was conducted using administrative and claims data from 11 U.S. health plans and corresponding birth certificate data from state health departments. Diagnoses, drug dispensings, and procedure codes were used to identify infant outcomes (cardiac defects, anencephaly, preterm birth, and neonatal intensive care unit [NICU] admission) and maternal diagnoses (asthma and systemic lupus erythematosus [SLE]) recorded in the health plan data for live born deliveries between January 2001 and December 2007. A random sample of medical charts (n = 802) was abstracted for infants and mothers identified with the specified outcomes. Information on newborn, maternal, and paternal characteristics (gestational age at birth, birth weight, previous pregnancies and live births, race/ethnicity) was also abstracted and compared to birth certificate data. Positive predictive values (PPVs) were calculated with documentation in the medical chart serving as the gold standard. RESULTS: PPVs were 71% for cardiac defects, 37% for anencephaly, 87% for preterm birth, and 92% for NICU admission. PPVs for algorithms to identify maternal diagnoses of asthma and SLE were ≥ 93%. Our findings indicated considerable agreement (PPVs > 90%) between birth certificate and medical record data for measures related to birth weight, gestational age, prior obstetrical history, and race/ethnicity. CONCLUSIONS: Health plan and birth certificate data can be useful to accurately identify some infant outcomes, maternal diagnoses, and newborn, maternal, and paternal characteristics. Other outcomes and variables may require medical record review for validation.

Medication exposure in pregnancy risk evaluation program: the prevalence of asthma medication use during pregnancy.

Asthma is one of the most common chronic diseases in women of reproductive age, occurring in up to 8 % of pregnancies. The objective of this study is to assess the prevalence of asthma medication use during pregnancy in a large diverse cohort. We identified women aged 15-45 years who delivered a live born infant between 2001 and 2007 across 11 U.S. health plans within the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). Using health plans' administrative and claims data, and birth certificate data, we identified deliveries for which women filled asthma medications from 90 days before pregnancy through delivery. Prevalence (%) was calculated for asthma diagnosis and medication dispensing. There were 586,276 infants from 575,632 eligible deliveries in the MEPREP cohort. Asthma prevalence among mothers was 6.7 %, increasing from 5.5 % in 2001 to 7.8 % in 2007. A total of 9.7 % (n = 55,914) of women were dispensed asthma medications during pregnancy. The overall prevalence of maintenance-only medication, rescue-only medication, and combined maintenance and rescue medication was 0.6, 6.7, and 2.4 % respectively. The prevalence of maintenance-only use doubled during the study period from 0.4 to 0.8 %, while rescue-only use decreased from 7.4 to 5.8 %. In this large population-based pregnancy cohort, the prevalence of asthma diagnoses increased over time. The dispensing of maintenance-only medication increased over time, while rescue-only medication dispensing decreased over time.

Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007.

OBJECTIVE: To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women. METHODS: Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates. RESULTS: A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P<.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P<.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy. CONCLUSIONS: Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance. LEVEL OF EVIDENCE: III.

The effectiveness of screening and brief intervention on reducing driving while intoxicated citations.

The purpose of this study was to use retrospective data, including citations for driving while intoxicated (DWI), to assess the long-term effectiveness of a program consisting of Screening and Brief Intervention (SBI) for at-risk alcohol users and its impact on traffic safety. A second objective was to study ethnic differences in response to SBI. During the time period of 1998-1999, LCF Research, together with the Lovelace Health System, participated in the Cutting Back SBI study for at-risk drinkers. A total of 426 subjects exhibiting at-risk drinking behaviors from the New Mexico cohort were examined for the study, including 211 subjects who received a brief counseling intervention and 215 in the no intervention control group. This study examined DWI citations for all 426 subjects during the 5 years following the Cutting Back study. The brief interventions were shown to have had a significant impact on reducing DWI citations for at-risk drinkers, with the added benefit lasting for the 5-year duration of the study. The SBI was found to be most effective at reducing DWI citations for Hispanic at-risk drinkers. Evidence is presented to show that screening to identify at-risk drinkers followed by a brief intervention has a statistically significant lasting impact on improving traffic safety.

Medication Exposure in Pregnancy Risk Evaluation Program.

To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.

Comparative effectiveness of patient education methods for type 2 diabetes: a randomized controlled trial.

BACKGROUND: Group education for patients with suboptimally controlled diabetes has not been rigorously studied. METHODS: A total of 623 adults from Minnesota and New Mexico with type 2 diabetes and glycosylated hemoglobin (HbA(1c)) concentrations of 7% or higher were randomized to (1) group education (using the US Diabetes Conversation Map program), (2) individual education, or (3) usual care (UC; ie, no assigned education). Both education methods covered content as needed to meet national standards for diabetes self-management education and were delivered through accredited programs from 2008 to 2009. General linear mixed-model methods assessed patient-level changes between treatment groups in mean HbA(1c) levels from baseline to follow-up at 6.8 months. Secondary outcomes included mean change in general health status (Medical Outcomes Study 12-Item Short Form Health Survey [SF-12]), Problem Areas in Diabetes (PAID), Diabetes Self-Efficacy (DES-SF), Recommended Food Score (RFS), and Physical Activity (PA, min/wk). RESULTS: Mean HbA(1c) concentration decreased in all groups but significantly more with individual (-0.51%) than group education (-0.27%) (P = .01) and UC (-0.24%) (P = .01). The proportion of subjects with follow-up HbA(1c) concentration lower than 7% was greater for individual education (21.2%) than for group (13.9%) and UC (12.8%) (P = .03). Compared with UC, individual education (but not group) improved SF-12 physical component score (+1.88) (P = .04), PA (+42.95 min/wk) (P = .03), and RFS (+0.63) (P = .05). Compared with group education, individual education reduced PAID (-3.62) (P = .02) and increased self-efficacy (+0.1) (P = .04). CONCLUSIONS: Individual education for patients with established suboptimally controlled diabetes resulted in better glucose control outcomes than did group education using Conversation Maps. There was also a trend toward better psychosocial and behavioral outcomes with individual education. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00652509.

Synergistic effect of statins and postmenopausal hormone therapy in the prevention of skeletal fractures in elderly women.

STUDY OBJECTIVE: To examine the role of concurrent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use and postmenopausal hormone therapy on osteoporosis-related fractures. DESIGN: Case-control study. Data Source. Large integrated health plan in New Mexico. Patients. Case patients were 1001 women with incident fractures of the hip, wrist, forearm, or spine that occurred between January 1, 2000, and December 31, 2005, and controls were 2607 women without fractures during the same time frame; both groups were selected from the same population of women aged 50 years or older who utilized health plan services during the study time frame. MEASUREMENTS AND MAIN RESULTS: Postmenopausal hormone therapy use was classified as "current" (12 mo before index date) or "never or past." The risk of fractures was ascertained among continuous (> or = 80% medication possession ratio during 12 mo before the index date) and current (3 mo before index date) statin users relative to patients without hyperlipidemia who did not use lipid-lowering drugs. The interaction between statins and hormone therapy was examined in multivariable logistic regression. The association between statin use and fractures was examined separately among current and never or past hormone therapy users after controlling for other risk factors. Nineteen percent of the study participants were current hormone therapy users; 9.5% were current and 4.8% were continuous statin users. No association between continuous statin use and fractures was observed among never or past hormone therapy users (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.53-1.22). In contrast, a strong protective effect (OR 0.19, 95% CI 0.04-0.87) was observed among women who concurrently used statins and hormone therapy for 1 year, independent of age; corticosteroid, bisphosphonate, thiazide diuretic, calcitonin, methotrexate, or antiepileptic drug use; chronic kidney disease; and Charlson comorbidity index. CONCLUSION: Concurrent statin use and hormone therapy may have a synergistic protective effect on skeletal fractures beyond the additive effect of each individual therapy.

A comparative analysis of recruitment methods used in a randomized trial of diabetes education interventions.

Recruitment methods heavily impact budget and outcomes in clinical trials. We conducted a post-hoc examination of the efficiency and cost of three different recruitment methods used in Journey for Control of Diabetes: the IDEA Study, a randomized controlled trial evaluating outcomes of group and individual diabetes education in New Mexico and Minnesota. Electronic databases were used to identify health plan members with diabetes and then one of the following three methods was used to recruit study participants: 1. Minnesota Method 1--Mail only (first half of recruitment period). Mailed invitations with return-response forms. 2. Minnesota Method 2--Mail and selective phone calls (second half of recruitment period). Mailed invitations with return-response forms and subsequent phone calls to nonresponders. 3. New Mexico Method 3--Mail and non-selective phone calls (full recruitment period): Mailed invitations with subsequent phone calls to all. The combined methods succeeded in meeting the recruitment goal of 623 subjects. There were 147 subjects recruited using Minnesota's Method 1, 190 using Minnesota's Method 2, and 286 using New Mexico's Method 3. Efficiency rates (percentage of invited patients who enrolled) were 4.2% for Method 1, 8.4% for Method 2, and 7.9% for Method 3. Calculated costs per enrolled subject were $71.58 (Method 1), $85.47 (Method 2), and $92.09 (Method 3). A mail-only method to assess study interest was relatively inexpensive but not efficient enough to sustain recruitment targets. Phone call follow-up after mailed invitations added to recruitment efficiency. Use of return-response forms with selective phone follow-up to non-responders was cost effective.

Cardiometabolic risk and health care utilization and cost for Hispanic and non-Hispanic women.

Cardiometabolic risk (CMR) is a specific set of risk factors that are associated with an increased chance of developing diabetes and cardiovascular disease. We conducted a retrospective study of female members of a health maintenance organization in the southwestern United States to: determine the prevalence of CMR for 4 different groupings of CMR factors, identify differences between Hispanics and non-Hispanics, and quantify differences in 2-year health care utilization and costs of CMR. Subjects were females who had bone mineral density tests during 2003-2004, and thus a measure of height and weight, allowing body mass index (BMI) calculation (n = 2578; 27.6% Hispanic). Risk factors used to define CMR groupings were: obesity (BMI), triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and fasting glucose. Results showed that Hispanics had higher prevalence rates than non-Hispanics (65.8% versus 52.3%, respectively; P < 0.0001). Adjusting for age and ethnicity, total costs for CMR patients in the groupings that required the presence of diabetes were twice the costs of those without CMR (approximately $11,500 versus $5500, respectively; P < 0.0001). In all other groupings, costs for patients with and without CMR were approximately $7000 versus $5500, respectively (P < 0.0001). Non-Hispanics had significantly higher visit costs than Hispanics. There were no differences in pharmacy costs. Higher utilization and costs associated with CMR suggest the need to identify and monitor patients with CMR. Our findings suggest diabetes prevention could yield substantial cost savings. Higher costs for non-Hispanics, despite higher prevalence among Hispanics, may indicate underutilization of health care resources by Hispanics. Future research in CMR should explore ethnic differences in access to care and disease management programs.

Administrative data used to identify patients with irritable bowel syndrome.

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.

Adequacy of glycemic, lipid, and blood pressure management for patients with diabetes in a managed care setting.

OBJECTIVE: We conducted a retrospective study to evaluate the adequacy of glycemic, lipid, and blood pressure (BP) management for diabetic patients in a managed care organization (MCO). RESEARCH DESIGN AND METHODS: Patients aged > or =18 years with diabetes (n=7,114) were retrospectively identified over a 2-year period from the MCO's administrative database based on the Health Plan Employer Data and Information Set 2000 selection criteria using pharmacy, laboratory, and encounter data. Analyses examined demographics and percentages of patients tested and meeting American Diabetes Association goals for HbA1c, lipids, and BP, both overall and for those receiving medication treatment versus no treatment. RESULTS: Testing rates for A1C, LDL cholesterol, and BP were 77, 54, and 95%, respectively. The percentage of patients tested who were at goal were 37% for A1C, 23% for LDL cholesterol, and 41% for systolic BP. Of the patients in our sample, 72% were treated for glycemic control, 64% were treated for BP control, and only 28% were treated for lipid control. Of the patients who received medication treatment, less than one-third were at goal for A1C (29%) and LDL cholesterol (32%), whereas 40% were at goal for systolic BP. CONCLUSIONS: We found that although a large percentage of diabetic patients were tested for A1C, LDL cholesterol, and systolic BP, a much smaller percentage had reached their respective goals. More aggressive glycemic, lipid, and BP management appears to be needed to improve care for these patients.

Management of osteoporosis in women aged 50 and older with osteoporosis-related fractures in a managed care population.

This study describes the pattern of evaluation and management of osteoporosis in women aged 50 and older following an osteoporosis-related fracture, conducted as a retrospective cohort study using the administrative claims database of a managed care organization. Subjects were women, aged 50 years and older, with at least one osteoporosis-related fracture in the years 1996-1998 who were continuously enrolled in the system's health plan for at least 6 months prior to and post-fracture. Bone mineral density (BMD) testing, diagnosis of osteoporosis, and treatment with any Food and Drug Administration-approved medication for osteoporosis were identified using CPT, ICD-9, and National Drug Codes for the 6-month post-fracture period. There were 658 women with an osteoporosis-related fracture: 189 (29%) hip fractures, 226 (34%) wrist fractures, 127 (19%) vertebral fractures, and 116 (18%) rib fractures. In the post-fracture period, 46 (7%) underwent BMD testing, 153 (23%) had a diagnosis of osteoporosis, and 220 (31%) were treated with a medication approved for the prevention or treatment of osteoporosis. Of the 220 women with medication claims, 124 (56%) were for estrogen, and 96 (44%) were for other antiresorptive agents. Of the 507 women who did not have medication claims during the 6 months prior to the fracture, only 17% had new fills after the fracture. Management of osteoporosis in women aged 50 and older with fractures was inadequate, despite the high risk of subsequent fractures and recommendations that osteoporosis be the presumptive diagnosis. Significant opportunity exists for improvement in assuring post-fracture followup care.