Kevin A. Peterson

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Primary Care Practice-Based Research Networks: Working at the Interface Between Research and Quality Improvement

PURPOSE We wanted to describe the emerging role of primary care practice-based in research, quality improvement (QI), and translation of research into practice (TRIP). METHODS We gathered information from the published literature, discussions with PBRN leaders, case examples, and our own personal experience to describe a role for PBRNs that comfortably bridges the gap between research and QI, discovery and application, academicians and practitioners—a role that may lead to the establishment of true learning communities. We provide specific recommendations for network directors, network clinicians, and other potential stakeholders. RESULTS PBRNs function at the interface between research and QI, an interface called TRIP by some members of the research community. In doing so, PBRNs are helping to clarify the difficulty of applying study findings to everyday care as an inappropriate disconnect between discovery and implementation, research and practice. Participatory models are emerging in which stakeholders agree on their goals; apply their collective knowledge, skills, and resources to accomplish these goals; and use research and QI methods when appropriate. CONCLUSIONS PBRNs appear to be evolving from clinical laboratories into learning communities, proving grounds for generalizable solutions to clinical problems, and engines for improvement of primary care delivery systems.

Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence

Specific mammalian genes functionally and dynamically associate together within the nucleus. Yet, how an array of many genes along the chromosome sequence can be spatially organized and folded together is unknown. We investigated the 3D structure of a well-annotated, highly conserved 4.3-Mb region on mouse chromosome 14 that contains four clusters of genes separated by gene “deserts.” In nuclei, this region forms multiple, nonrandom “higher order” structures. These structures are based on the gene distribution pattern in primary sequence and are marked by preferential associations among multiple gene clusters. Associating gene clusters represent expressed chromatin, but their aggregation is not simply dependent on ongoing transcription. In chromosomes with aggregated gene clusters, gene deserts preferentially align with the nuclear periphery, providing evidence for chromosomal region architecture by specific associations with functional nuclear domains. Together, these data suggest dynamic, probabilistic 3D folding states for a contiguous megabase-scale chromosomal region, supporting the diverse activities of multiple genes and their conserved primary sequence organization.

High-throughput discovery of novel developmental phenotypes.

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Management of type 2 diabetes in the primary care setting: A practice-based research network study

PURPOSE We wanted to describe how primary care clinicians care for patients with type 2 diabetes. METHODS We undertook a cross-sectional study of 95 primary care clinicians and 822 of their established patients with type 2 diabetes from 4 practice-based, primary care research networks in the United States. Clinicians were surveyed about their training and practice. Patients completed a self-administered questionnaire about their care, and medical records were reviewed for complications, treatment, and diabetes-control indicators. RESULTS Participating clinicians (average age, 45.7 years) saw an average of 32.6 adult patients with diabetes per month. Patients (average age, 59.7 years) reported a mean duration of diabetes of 9.1 years, with 34.3% having had the disease more than 10 years. Nearly one half (47.5%) of the patients had at least 1 diabetes-related complication, and 60.8% reported a body mass index greater than 30. Mean glycosylated hemoglobin (HbA1c) level was 7.6% (SD 1.73), and 40.5% of patients had values <7%. Only 35.3% of patients had adequate blood pressure control (<130/85 mm Hg), and only 43.7% had low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL. Only 7.0% of patients met all 3 control targets. Multilevel models showed that patient ethnicity, practice type, involvement of midlevel clinicians, and treatment were associated with HbA1c level; patient age, education level, and practice type were associated with blood pressure control; and patient ethnicity was associated with LDL-C control. CONCLUSIONS Only modest numbers of patients achieve established targets of diabetes control. Reengineering primary care practice may be necessary to substantially improve care.

Improving Diabetes Care in Practice: Findings from the TRANSLATE trial

OBJECTIVE—The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practices. RESEARCH DESIGN AND METHODS—This was a group-randomized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention (TRANSLATE) in 24 practices. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure (SBP) <130 mmHg, LDL cholesterol <100 mg/dl, and A1C <7.0% at baseline and 12 months. Six process measures were also followed. RESULTS—Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practices from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practices, giving net increases as follows: foot examinations 35.0% (P < 0.0.001); annual eye examinations 25.9% (P < 0.001); renal testing 28.5% (P < 0.001); A1C testing 8.1%(P < 0.001); blood pressure monitoring 3.5% (P = 0.05); and LDL testing 8.6% (P < 0.001). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practices (P < 0.02). At 12 months, intervention practices had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics (P = 0.002). CONCLUSIONS—Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes.

Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning

In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination and neural tube patterning. Functional analysis in transgenic mice validates core enhancers for each of these factors and demonstrates the dual requirement for Gli1 and Sox2 inputs for neural enhancer activity. Furthermore, through an unbiased determination of Gli-binding site preferences and analysis of binding site variants in the developing mammalian CNS, we demonstrate that differential Gli-binding affinity underlies threshold-level activator responses to Shh input. In summary, our results highlight Sox2 input as a context-specific determinant of the neural-specific Shh response and differential Gli-binding site affinity as an important cis-regulatory property critical for interpreting Shh morphogen action in the mammalian neural tube.

Evidence for a Conserved Function in Synapse Formation Reveals Phr1 as a Candidate Gene for Respiratory Failure in Newborn Mice

ABSTRACT Genetic studies using a set of overlapping deletions centered at the piebald locus on distal mouse chromosome 14 have defined a genomic region associated with respiratory distress and lethality at birth. We have isolated and characterized the candidate gene Phr1 that is located within the respiratory distress critical genomic interval. Phr1 is the ortholog of the human Protein Associated with Myc as well as Drosophila highwire and Caenorhabditis elegans regulator of presynaptic morphology 1. Phr1 is expressed in the embryonic and postnatal nervous system. In mice lacking Phr1, the phrenic nerve failed to completely innervate the diaphragm. In addition, nerve terminal morphology was severely disrupted, comparable with the synaptic defects seen in the Drosophila hiw and C. elegans rpm-1 mutants. Although intercostal muscles were completely innervated, they also showed dysmorphic nerve terminals. In addition, sensory neuron terminals in the diaphragm were abnormal. The neuromuscular junctions showed excessive sprouting of nerve terminals, consistent with inadequate presynaptic stimulation of the muscle. On the basis of the abnormal neuronal morphology seen in mice, Drosophila, and C. elegans, we propose that Phr1 plays a conserved role in synaptic development and is a candidate gene for respiratory distress and ventilatory disorders that arise from defective neuronal control of breathing.

The Impact of Frequent and Unrecognized Hypoglycemia on Mortality in the ACCORD Study

OBJECTIVE The aim of this study was to examine the relationship between frequent and unrecognized hypoglycemia and mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study cohort. RESEARCH DESIGN AND METHODS A total of 10,096 ACCORD study participants with follow-up for both hypoglycemia and mortality were included. Hazard ratios (95% CIs) relating the risk of death to the updated annualized number of hypoglycemic episodes and the updated annualized number of intervals with unrecognized hypoglycemia were obtained using Cox proportional hazards regression models, allowing for these hypoglycemia variables as time-dependent covariates and controlling for the baseline covariates. RESULTS Participants in the intensive group reported a mean of 1.06 hypoglycemic episodes (self-monitored blood glucose <70 mg/dL or <3.9 mmol/L) in the 7 days preceding their regular 4-month visit, whereas participants in the standard group reported an average of 0.29 episodes. Unrecognized hypoglycemia was reported, on average, at 5.8% of the intensive group 4-month visits and 2.6% of the standard group visits. Hazard ratios for mortality in models including frequency of hypoglycemic episodes were 0.93 (95% CI 0.9–0.97; P < 0.001) for participants in the intensive group and 0.98 (0.91–1.06; P = 0.615) for participants in the standard group. The hazard ratios for mortality in models, including unrecognized hypoglycemia, were not statistically significant for either group. CONCLUSIONS Recognized and unrecognized hypoglycemia was more common in the intensive group than in the standard group. In the intensive group of the ACCORD study, a small but statistically significant inverse relationship of uncertain clinical importance was identified between the number of hypoglycemic episodes and the risk of death among participants.

Targeting β-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus

OBJECTIVE This report examines current perspectives regarding likely mechanisms of beta-cell failure in type 2 diabetes and their clinical implications for protecting or sparing beta-cells early in the disease progression. In addition, it considers translation strategies to incorporate relevant scientific findings into educational initiatives targeting clinical practice behavior. PARTICIPANTS On January 10, 2009, a working group of basic researchers, clinical endocrinologists, and primary care physicians met to consider whether current knowledge regarding pancreatic beta-cell defects justifies retargeting and retiming treatment for clinical practice. Based on this meeting, a writing group comprised of four meeting participants subsequently prepared this consensus statement. The conference was convened by The Endocrine Society and funded by an unrestricted educational grant from Novo Nordisk. EVIDENCE Participants reviewed and discussed published literature, plus their own unpublished data. CONSENSUS PROCESS The summary and recommendations were supported unanimously by the writing group as representing the consensus opinions of the working group. CONCLUSIONS Workshop participants strongly advocated developing new systems to address common barriers to glycemic control and recommended several initial steps toward this goal. These recommendations included further studies to establish the clinical value of pharmacological therapies, continuing basic research to elucidate the nature and mechanisms of beta-cell failure in type 2 diabetes mellitus, and exploring new educational approaches to promote pathophysiology-based clinical practices. The Endocrine Society has launched a new website to continue the discussion between endocrinologists and primary care physicians on beta-cell pathophysiology in type 2 diabetes and its clinical implications. Join the conversation at http://www.betacellsindiabetes.org