Gregory S. Calip

Adherence to oral diabetes medications and glycemic control during and following breast cancer treatment

We evaluated changes in oral diabetes mellitus medication adherence and persistence, as well as glycemic control for the year prior to breast cancer (BC) diagnosis (Year −1), during BC treatment, and in subsequent years.

Effect of Treatment and Mammography Detection on Breast Cancer Survival Over Time: 1990-2007

The extent to which improvements over time in breast cancer survival are related to earlier detection by mammography or to more effective treatments is not known.

Indications For and Use of Nonsteroidal Antiinflammatory Drugs and the Risk of Incident, Symptomatic Benign Prostatic Hyperplasia: Results From the Prostate Cancer Prevention Trial

The authors conducted a cohort study of nonsteroidal antiinflammatory drug (NSAID) use and risk of symptomatic benign prostatic hyperplasia (BPH), using data from 4,735 men without BPH at baseline in the placebo arm of the Prostate Cancer Prevention Trial (1993-2003). Incident BPH (n = 471) was defined as medical or surgical treatment or at least 2 International Prostate Symptom Score (I-PSS) values greater than or equal to 15. Proportional hazards models using time-dependent exposure for NSAID use were employed to estimate covariate-adjusted associations of NSAID-related medical conditions and NSAID use with BPH risk. Arthritis, other inflammation-related musculoskeletal conditions, and headaches were associated with increased BPH risk (hazard ratio (HR) = 1.77 (95% confidence interval (CI): 1.37, 2.29), HR = 1.57 (95% CI: 1.14, 2.17), and HR = 1.40 (95% CI: 1.09, 1.80), respectively). Use of any NSAID, use of aspirin, and use of nonaspirin NSAIDs were associated with significant increases in BPH risk (HR = 1.21 (95% CI: 1.01, 1.46), HR = 1.20 (95% CI: 1.00, 1.45), and HR = 1.34 (95% CI: 1.07, 1.69), respectively). Control for indications for NSAID use, including baseline I-PSS, attenuated the associations slightly, but all became nonsignificant. Among men with no indications for NSAID use, the hazard ratio for any NSAID use was 1.06 (95% CI: 0.82, 1.38). The modest associations of NSAID use with BPH risk in this cohort were probably due to confounding by indication, and NSAID use was not associated with BPH risk.

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

Background Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. Methods and findings Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08–1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36–1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6–12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54–2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26–2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52–2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%–3.5%]) and quinine exposures (1.2% [95% CI 0.6%–2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. Conclusions Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. Review registration PROSPERO CRD42015032371

Medication adherence and persistence over time with self-administered TNF-alpha inhibitors among young adult, middle-aged, and older patients with rheumatologic conditions

OBJECTIVE Self-injectable TNF inhibitors are increasingly used early in the chronic treatment of moderate to severe rheumatologic conditions. We estimated medication adherence/persistence over time following initiation in young adult and older adult patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis. METHODS We conducted a retrospective cohort study of patients aged 18+ years newly initiating etanercept, adalimumab, certolizumab pegol, or golimumab using the Truven Health MarketScan Database between 2009 and 2013. Pharmacy dispensing data were used to calculate 12-month medication possession ratios (MPR) and determine adherence (MPR ≥ 0.80) for up to 3 years after starting therapy. Persistence over each 12-month interval was defined as not having a ≥92-day treatment gap. Multivariable generalized estimating equation models were used to calculate odds ratios (OR) and robust 95% confidence intervals (CI) for associations between patient characteristics and repeated adherence/persistence measures over time. RESULTS Among 53,477 new users, 14% were young adults (18-34 years), 49% middle-aged (35-54 years), and 37% older adults (55+ years). Overall, 37% of patients were adherent and 83% were persistent in the first year of therapy. The lowest adherence (17%) and persistence (70%) were observed among young adult patients by Year +3. Compared to older adults, middle-aged (OR = 0.73, 95% CI: 0.71-0.76) and young adults (OR = 0.50, 95% CI: 0.47-0.53) were less likely to be adherent. Higher Charlson comorbidity scores, hospitalizations, and emergency department visits were associated with non-adherence/non-persistence. CONCLUSIONS We observed low adherence to self-administered TNF inhibitors but most patients remained persistent over time. Further efforts to improve adherence in young adults and patients with greater comorbidity are needed.

Weekly miscarriage rates in a community-based prospective cohort study in rural western Kenya.

Objective Information on adverse pregnancy outcomes is important to monitor the impact of public health interventions. Miscarriage is a challenging end point to ascertain and there is scarce information on its rate in low-income countries. The objective was to estimate the background rate and cumulative probability of miscarriage in rural western Kenya. Design This was a population-based prospective cohort. Participants and setting Women of childbearing age were followed prospectively to identify pregnancies and ascertain their outcomes in Siaya County, western Kenya. The cohort study was carried out in 33 adjacent villages under health and demographic surveillance. Outcome measure Miscarriage. Results Between 2011 and 2013, among 5536 women of childbearing age, 1453 pregnancies were detected and 1134 were included in the analysis. The cumulative probability was 18.9%. The weekly miscarriage rate declined steadily with increasing gestation until approximately 20 weeks. Known risk factors for miscarriage such as maternal age, gravidity, occupation, household wealth and HIV infection were confirmed. Conclusions This is the first report of weekly miscarriage rates in a rural African setting in the context of high HIV and malaria prevalence. Future studies should consider the involvement of community health workers to identify the pregnancy cohort of early gestation for better data on the actual number of pregnancies and the assessment of miscarriage.

Assessment of the safety of antimalarial drug use during early pregnancy (ASAP): protocol for a multicenter prospective cohort study in Burkina Faso, Kenya and Mozambique

BackgroundA major unresolved safety concern for malaria case management is the use of artemisinin combination therapies (ACTs) in the first trimester of pregnancy. There is a need for human data to inform policy makers and treatment guidelines on the safety of artemisinin combination therapies (ACT) when used during early pregnancy.MethodsThe overall goal of this paper is to describe the methods and implementation of a study aimed at developing surveillance systems for identifying exposures to antimalarials during early pregnancy and for monitoring pregnancy outcomes using health and demographic surveillance platforms.This was a multi-center prospective observational cohort study involving women at health and demographic surveillance sites in three countries in Africa: Burkina Faso, Kenya and Mozambique [(ClinicalTrials.gov Identifier: NCT01232530)]. The study was designed to identify pregnant women with artemisinin exposure in the first trimester and compare them to: 1) pregnant women without malaria, 2) pregnant women treated for malaria, but exposed to other antimalarials, and 3) pregnant women with malaria and treated with artemisinins in the 2nd or 3rd trimesters from the same settings. Pregnant women were recruited through community-based surveys and attendance at health facilities, including antenatal care clinics and followed until delivery. Data from the three sites will be pooled for analysis at the end of the study. Results are forthcoming.DiscussionDespite few limitations, the methods described here are relevant to the development of sustainable pharmacovigilance systems for drugs used by pregnant women in the tropics using health and demographic surveillance sites to prospectively ascertain drug safety in early pregnancy.Trial registrationNCT01232530

Therapy-related myelodysplastic syndrome following primary breast cancer

BACKGROUND Therapy-related myelodysplastic syndrome (t-MDS) is a serious clinical disease occurring after breast cancer treatment. METHODS A cohort of 11,684 invasive breast cancer (BC) patients from 1990-2014 were followed for incidence of t-MDS through institutional and the Surveillance, Epidemiology and End Results (SEER) Program registries. t-MDS cases were identified using ICD-O SEER registry codes, pathology and chart reports. Treatment, cytogenetics, and time from BC diagnosis to t-MDS and t-MDS diagnosis to last follow up or death were obtained. Incidence rate ratios were calculated using SEER national incidence rates for comparison. RESULTS 27 cases of t-MDS post BC treatment were confirmed. 96% of cases were breast cancer stage I-II at diagnosis. All patients had received radiation treatment and 59% received adjuvant chemotherapy. Two patients were alive with no evidence of disease after treatment with stem cell transplantation (age 33 and 46). t-MDS incidence was 30 times the expected population rate among patients <55 years (RR 31.8, 95% CI 15.0, 60.8) with shorter time from t-MDS diagnosis to death (median survival time: <55: 8 months, 55-74: 26 months, 75+: 23 months). CONCLUSION We found elevated t-MDS risk especially among younger BC patients with stem cell transplantation the only observed curative treatment.

Comparative Effectiveness of Long‐Acting Beta2‐Agonist Combined with a Long‐Acting Muscarinic Antagonist or Inhaled Corticosteroid in Chronic Obstructive Pulmonary Disease

Several dual bronchodilator fixed‐dose inhaler medications were recently approved for the treatment of chronic obstructive pulmonary disease (COPD). These products combine a long‐acting β2‐agonist (LABA) and long‐acting muscarinic antagonist (LAMA). In clinical trials, the separate mechanisms of the bronchodilators resulted in improved lung function. COPD treatment guidelines currently recommend combination LABA/LAMA as alternative therapy to combination LABA/inhaled corticosteroid (ICS). Evidence is limited on the comparative effectiveness of LABA/LAMA and LABA/ICS in COPD. The objective of this study was to compare real‐world COPD exacerbation rates among patients treated with LABA/LAMA with those treated with LABA/ICS.

Impact of the Family Health Program on gastroenteritis in children in Bahia, Northeast Brazil: an analysis of primary care-sensitive conditions.

In seeking to provide universal health care through its primary care-oriented Family Health Program, Brazil has attempted to reduce hospitalization rates for preventable illnesses such as childhood gastroenteritis. We measured rates of Primary Care-sensitive Hospitalizations and evaluated the impact of the Family Health Program on pediatric gastroenteritis trends in high-poverty Northeast Brazil. We analyzed aggregated municipal-level data in time-series between years 1999–2007 from the Brazilian health system payer database and performed qualitative, in-depth key informant interviews with public health experts in municipalities in Bahia. Data were sampled for Bahia’s Salvador microregion, a population of approximately 14 million. Gastroenteritis hospitalization rates among children aged less than 5 years were evaluated. Declining hospitalization rates were associated with increasing coverage by the PSF (P = 0.02). After multivariate adjustment for garbage collection, sanitation, and water supply, evidence of this association was no longer significant (P = 0.28). Qualitative analysis confirmed these findings with a framework of health determinants, proximal causes, and health system effects. The PSF, with other public health efforts, was associated with decreasing gastroenteritis hospitalizations in children. Incentives for providers and more patient-centered health delivery may contribute to strengthening the PSF’s role in improving primary health care outcomes in Brazil.