Christopher Miller

PURPOSE: The purpose of this study was to determine whether "clinical inertia"-inadequate intensification of therapy by the provider-could contribute to high A1C levels in patients with type 2 diabetes managed in a primary care site. METHODS: In a prospective observational study, management was compared in the Medical Clinic, a primary care site supervised by general internal medicine faculty, and the Diabetes Clinic, a specialty site supervised by endocrinologists. These municipal hospital clinics serve a common population that is largely African American, poor, and uninsured. RESULTS: Four hundred thirty-eight African American patients in the Medical Clinic and 2157 in the Diabetes Clinic were similar in average age, diabetes duration, body mass index, and gender, but A1C averaged 8.6% in the Medical Clinic versus 7.7% in the Diabetes Clinic (P < .0001). Use of pharmacotherapy was less intensive in the Medical Clinic (less use of insulin), and when patients had elevated glucose levels during clinic visits, therapy was less than half as likely to be advanced in the Medical Clinic compared to the Diabetes Clinic (P < .0001). Intensification rates were lower in the Medical Clinic regardless of type of therapy (P < .0001), and intensification of therapy was independently associated with improvement in A1C (P < .001). CONCLUSIONS: Medical Clinic patients had worse glycemic control, were less likely to be treated with insulin, and were less likely to have their therapy intensified if glucose levels were elevated. To improve diabetes management and glycemic control nationwide, physicians in training and generalists must learn to overcome clinical inertia, to intensify therapy when appropriate, and to use insulin when clinically indicated.

Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics.

BACKGROUND: Type 2 diabetes mellitus is highly prevalent in minority populations in the United States. We studied the relationship of age to glycemic control in a predominantly urban African American population with type 2 diabetes. METHODS: We selected all patients with type 2 diabetes who were enrolled in the Grady Diabetes Clinic, Atlanta, Ga, between April 1, 1991, and December 31, 1998, and had a hemoglobin A(1c) (HbA(1c)) level measured at their initial visit and at follow-up 5 to 12 months later (n = 2539). Patients were divided into 4 age categories: less than 30 years, 30 to 49 years, 50 to 69 years, and more than 69 years old. We also studied the relationship of age to HbA(1c) level in a primary care clinic. RESULTS: At baseline, average HbA(1c) levels were 9.9%, 9.5%, 9.2%, and 8.8% in the 4 groups ranked in increasing age, respectively (P<.001), and body mass indexes (calculated as weight in kilograms divided by the square of height in meters) were 37.8, 33.9, 31.6, and 29.2, respectively (P<.001). On follow-up, HbA( 1c) level improved in all groups (P<.001), but there was still a trend for younger patients to have higher levels of HbA(1c). There was little change in body mass index with time. Younger age, longer diabetes duration, higher body mass index, less frequent interval visits, and treatment with oral agents or insulin were associated with a higher HbA(1c) level at follow-up. Our findings in a primary care clinic showed also that HbA( 1c) level and body mass index were negatively correlated with age (P<.001). CONCLUSION: Our data show a high prevalence of obesity and poor glycemic control in young adult urban African Americans with diabetes.

STUDY OBJECTIVES: To identify the prevalence and types of clinically significant drug interactions (CSDIs) in the drug regimens of patients with human immunodeficiency virus (HIV) infection who were receiving antiretroviral therapy, and to explore risk factors for these CSDIs. DESIGN: Retrospective medical record review. SETTING: Academic HIV specialty clinic. PATIENTS: One hundred fifty-three randomly selected patients with HIV infection who were receiving antiretroviral therapy from May 1-September 30, 2006. MEASUREMENTS AND MAIN RESULTS: Data were collected on patient demographics, date of HIV diagnosis, most recent viral load and CD4(+) count, Centers for Disease Control and Prevention HIV classification, and comorbid conditions. Patients' drug regimens were analyzed for total and clinically significant antiretroviral drug interactions using three resources. Logistic regression and classification and regression tree analysis were used to identify independent CSDI predictors. Clinically significant drug interactions were defined as drug interactions that required a dosage adjustment or consisted of a drug combination that is contraindicated due to its high potential for clinical adverse effects. Of the 153 patients, at least one CSDI was found in 41.2% of their regimens: 34.6% with at least one drug interaction that required a dosage adjustment, 2.0% with at least one contraindicated drug combination, and 4.6% with at least one of each of these CSDIs. In the logistic regression model, risk factors independently associated with CSDIs were age older than 42 years (odds ratio [OR] 2.9, 95% CI 1.2-7.1), more than three comorbid conditions (OR 3.0, 95% CI 1.4-6.6), treatment with more than three antiretroviral agents (OR 2.4, 95% CI 1.0-5.8), and treatment with a protease inhibitor (OR 11.5, 95% CI 4.2-31.2). When directly compared, CSDIs were more prevalent among protease inhibitor-based than nonnucleoside reverse transcriptase inhibitor-based regimens (p<0.001). CONCLUSION: Clinically significant drug interactions are highly prevalent among HIV-infected patients receiving antiretroviral therapy. Knowledge of the risk factors for CSDIs may help clinicians recognize and manage CSDIs.

Candida esophagitis, a defining illness of acquired immunodeficiency syndrome (AIDS), requires systemic antifungal therapy. Candida albicans can become resistant to commonly administered azole antifungal agents. An attractive alternative is caspofungin, an echinocandin antifungal that has generally displayed predictable activity against C. albicans. We report the case of a 29-year-old woman with AIDS who developed recurrent esophagitis caused by a strain of C. albicans that showed reduced susceptibility to caspofungin (elevated minimum inhibitory concentration of 8 mg/L). Analysis of the strain revealed that it contained a serine-to-proline substitution at position 645 in the FKS1 gene. Clinicians who prescribe caspofungin to treat esophagitis caused by C. albicans should recognize the potential risk, albeit slight, for acquired resistance to caspofungin and possibly other echinocandin antifungal agents in the face of persistent disease. In patients who are refractory or unresponsive to caspofungin therapy, susceptibility testing and/or alternative therapy should be considered.