ABSTRACT
Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.
Subject(s)
Antitubercular Agents/pharmacology , Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Inhibins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , NAD/metabolism , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Inhibins/metabolism , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/enzymology , Structure-Activity Relationship , Tuberculosis, Multidrug-Resistant/enzymologyABSTRACT
Increased access to insurance under the Affordable Care Act will increase demands for clinical services in community health centers (CHCs). CHCs also have an increasingly important educational role to train clinicians who will remain to practice in community clinics. CHCs and Area Health Education Centers (AHECs) are logical partners to prepare the health workforce for the future. Both are sponsored by the Health Resources and Services Administration, and they share a mission to improve quality of care in medically underserved communities. AHECs emphasize the educational side of the mission, and CHCs the service side. Building stronger partnerships between them can facilitate a balance between education and service needs.From 2004 to 2011, the California Statewide AHEC program and its 12 community AHECs (centers) reorganized to align training with CHC workforce priorities. Eight centers merged into CHC consortia; others established close partnerships with CHCs in their respective regions. The authors discuss issues considered and approaches taken to make these changes. Collaborative innovative processes with program leadership, staff, and center directors revised the program mission, developed common training objectives with an evaluation plan, and defined organizational, functional, and impact characteristics for successful AHECs in California. During this planning, centers gained confidence as educational arms for the safety net and began collaborations with statewide programs as well as among themselves. The AHEC reorganization and the processes used to develop, strengthen, and identify standards for centers forged the development of new partnerships and established academic-community trust in planning and implementing programs with CHCs.
Subject(s)
Area Health Education Centers , Community Health Services/organization & administration , Community-Institutional Relations , California , Health Priorities , Health Services Accessibility , Health Services Needs and Demand , Humans , Organizational Innovation , Organizational Objectives , Program Development , Program EvaluationABSTRACT
BACKGROUND AND OBJECTIVES: Diagnosis and treatment of pediatric mental, physical, and behavioral issues are essential for optimal growth and development. Our family medicine residency program implemented a change in our pediatric curriculum by incorporating aspects of Healthy Steps into well-child visits 1 day a week. This study was done to determine the impact on developmental referral rates after incorporating Healthy Steps. METHODS: We did a retrospective medical records review at a rural California family medicine residency clinic on children through 5 years of age receiving well-child care. We collected developmental referrals as documented in the chart and in a referral log for 1 year before the curriculum change and 3 years after implementation. This retrospective case-control study included a pre-intervention group (Pre) and two post-intervention groups, usual care control (UC) and Healthy Steps intervention (HS). The three groups were compared using Fisher's exact tests. RESULTS: Developmental referrals assessed by chart review were 0% (0/154) in Pre, 0.6% (1/159) in UC, and 5.4% (4/74) in HS groups. When assessed by referral logs, developmental referral rates were 1.2% (10/864) in Pre, 1.1% (14/1,251) in UC, and 9.9% (14/141) in HS groups. For both sources, the HS group had significantly higher referral rates than the other groups. There was no statistical difference in referrals between the Pre and UC groups. CONCLUSIONS: After incorporating aspects of Healthy Steps into our curriculum, developmental referrals rose significantly in the intervention group compared to pre-intervention. Referral rates did not change in the non-intervention control group.
